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

Central Nervous System Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01527006
• Other study ID #: E2007-G000-232
• Status: Completed
• Phase: Phase 2
• First received: November 10, 2011
• Last updated: February 10, 2016
• Start date: February 2012
• Est. completion date: April 2015

Study information

• Verified date: February 2016
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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

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). All subjects who completed all scheduled visits up to and including the final visit of the Treatment Phase (Core Study) were eligible to participate in the Extension Phase of the study. The Extension Phase consisted of 2 periods: Maintenance (41 weeks) and Follow-up (4 weeks).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 63
• Est. completion date: April 2015
• Est. primary completion date: May 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 2 Years to 11 Years

Eligibility

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

Study Design

Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Central Nervous System

Intervention

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. During the extension phase, participants continued taking perampanel oral suspension once daily, at the dose level achieved at the end of the treatment phase of the core study to a maximum daily dose of 0.18 mg/kg. The maximum total daily dose a participant was allowed was 12 mg.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Eisai Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	The Effect of Demographics on Population PK Parameters: AUC	This outcome was not assessed in the study.	11 weeks	No
Other	The Effect of Demographics on Population PK Parameters: Cmax	This outcome was not assessed in the study.	11 weeks	No
Other	The Effect of Demographics on Population PK Parameters: Tmax	This outcome was not assessed in the study.	11 weeks	No
Other	The Effect of the Most Common Concomitant AEDs on Population PK Parameters: AUC	This outcome was not assessed in the study.	11 weeks	No
Other	The Effect of the Most Common Concomitant AEDs on Population PK Parameters: Cmax	This outcome was not assessed in the study.	11 weeks	No
Other	The Effect of the Most Common Concomitant AEDs on Population PK Parameters: Tmax	This outcome was not assessed in the study.	11 weeks	No
Primary	Apparent Clearance (CL/F) of Perampanel [Core Study]	CL/F was defined as the volume of plasma cleared of the drug per unit time. Blood samples were collected at day 8, Day 36, Day 64 , and Day 78. 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.	From Day 8 up to Day 78	No
Primary	Steady-state Average Concentration (C av,ss) of Perampanel [Core Study]	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). Blood samples were collected at day 8, Day 36, Day 64 , and Day 78. C av,ss values were calculated for each visit and averaged to derive the total C av,ss value per arm. 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.	From Day 8 up to Day 78	No
Secondary	Percent Change From Baseline in Seizure Frequency Per 28 Days in Treatment Phase [Core Study]	Seizure frequency was derived from information (seizure count and type) recorded in participant diary. The seizure frequency per 28 days was calculated the number of seizures over the time interval multiplied by 28 and divided by the number of days in the interval. 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.	Baseline [2 weeks Pretreatment Phase (Visit 1) plus 4 weeks Prior to Pretreatment Phase], Week 0 to Week 15	No
Secondary	50% Responder Rate During the Maintenance Period-LOCF [Core Study]	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.	Baseline [2 weeks Pretreatment Phase (Visit 1) plus 4 weeks Prior to Pretreatment Phase], Week 9 to 11	No
Secondary	Seizure-free Rate During the Maintenance Period [Core Study]	Seizure-free rate, defined as the percentage of participants who were seizure-free during the Maintenance Period. SG = Secondary Generalization.	Week 9 to Week 11	No
Secondary	The Clinical Global Impression of Change at the End of Treatment (EOT) [Core Study]	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 (Week 0). 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 EOT (the duration after the day of first study drug dose up to 7 days after the last Core Phase drug dose, inclusive). 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 (Week 0).	Week 0 (Baseline), Week 11 or EOT	No
Secondary	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	An AE was defined as any untoward medical occurrence in a participant administered with the study drug. 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 (serious/non-serious) that started/increased in severity on/after the first dose of study drug up to 30 days after the final dose of study drug) were assessed. The details of the adverse events are presented in the safety section of the results.	For each participant, from the first treatment dose till 30 days after the last dose or up to Week 15 for Core Study and Week 56 for the Extension Phase	Yes
Secondary	Palatability Questionnaire Assessment - How Does This Medicine Taste [Core Study]	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).	Week 5 or at the time of early discontinuation	No
Secondary	Palatability Questionnaire Assessment - How Does This Medicine Smell [Core Study]	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).	Week 5 or at the time of early discontinuation	No
Secondary	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 [Core Study]	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).	Week 5 or at the time of early discontinuation	No
Secondary	Palatability Questionnaire Assessment - Would You/Your Child Have Preferred This Medicine to Have Been Flavored, e.g. Fruity [Core Study]	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).	Week 5 or at the time of early discontinuation	No
Secondary	Percentage Change From Baseline in Seizure Frequency Per 28 Days During the Overall Treatment Duration by 13-week Intervals [Extension Phase]	Seizure frequency was derived from information (seizure count and type) recorded in participant diary. The seizure frequency per 28 days was calculated the number of seizures over the time interval multiplied by 28 and divided by the number of days in the interval. 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.	Baseline [2 weeks Pretreatment Phase (Visit 1) plus 4 weeks Prior to Pretreatment Phase], Weeks 1-13, Weeks 14-26, Weeks 27-39, and Weeks 40-52	No
Secondary	50 % Responder Rate During the Overall Treatment Duration by 13-week Intervals [Extension Phase]	Responder rate was defined as the proportion of participants with a 50% decrease in 28-day seizure frequency during the overall treatment duration. The percentage of responders was assessed from Week 1 of perampanel treatment through successive 13-week intervals for overall seizures, overall partial seizures, overall generalized seizures, and unclassified seizures with baseline as Pretreatment Phase (Visit 1) of 2 weeks plus 4 weeks Prior to Pretreatment Phase. The data is presented as percentage of responders.	Baseline [2 weeks Pretreatment Phase (Visit 1) plus 4 weeks Prior to Pretreatment Phase], Weeks 1-13, Weeks 14-26, Weeks 27-39, and Weeks 40-52	No
Secondary	Seizure-free Rate During the Overall Treatment Duration [Extension Phase]	Seizure-free rate, defined as the percentage of participants who were seizure-free during the Maintenance Period. The percentage of participants who were seizure free was assessed from Week 1 of perampanel treatment through successive 13-week intervals for overall seizures, overall partial seizures, overall generalized seizures, and unclassified seizures with baseline as Pretreatment Phase (Visit 1) of 2 weeks plus 4 weeks Prior to Pretreatment Phase. The data is presented as the percentage of participants.	Baseline [2 weeks Pretreatment Phase (Visit 1) plus 4 weeks Prior to Pretreatment Phase], Weeks 1-13, Weeks 14-26, Weeks 27-39, and Weeks 40-52	No
Secondary	The Clinical Global Impression of Change During the Overall Treatment Duration by Visit and at EOT [Extension Phase]	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 (Week 0). 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 planned visit and at EOT (the duration after the day of first study drug dose up to 7 days after the Extension Phase drug dose, inclusive). 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 the planned/EOT visits compared to Baseline (Week 0).	Week 0 (Baseline), Week 11, Week 28, Week 52 or EOT	No