A Study With an Open-label Extension Phase to Evaluate the Effect of Perampanel (E2007) on Cognition, Growth, Safety, Tolerability, and Pharmacokinetics in Adolescents

Epilepsy Clinical Trial

Official title:

A Randomized, Double-blind, Placebo-controlled, Parallel-group Study With an Open-label Extension Phase to Evaluate the Effect of Perampanel (E2007) on Cognition, Growth, Safety, Tolerability, and Pharmacokinetics When Administered as an Adjunctive Therapy in Adolescents (12 to Less Than 18 Years of Age) With Inadequately Controlled Partial-onset Seizures

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01161524
• Other study ID #: E2007-G000-235
• Status: Completed
• Phase: Phase 2
• Start date: September 2010
• Est. completion date: November 2014

Study information

• Verified date: November 2015
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is designed to investigate the short- and long-term effects of perampanel on cognition, growth, and development in adolescents.

Description:

This study consisted of the Core Study and the Extension Part A and B. The Core Study consisted of 2 phases: Prerandomization and Randomization. The Prerandomization Phase lasted up to 1 week, during which participants were assessed for their eligibility to participate in the study. The Randomization Phase consisted of 3 periods: Titration (6 weeks), Maintenance (13 weeks), and Follow-up (4 weeks; only for those participants not rolling over into the Extension Phase). During the Core Study Titration and Maintenance Periods, participants were randomized into perampanel (2 to 12 mg per day) or placebo treatment groups in a 2:1 ratio within each of the age-matched categories (ie, greater than or equal to 12 to less than 15 and greater than or equal to 15 to less than 18).

The extension phase consisted of part A (Conversion Period - 6 weeks and Maintenance period - 25 weeks) and Part B (Optional Extension Phase -52 weeks). The maximum duration for participation in Part B was 52 weeks.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 133
• Est. completion date: November 2014
• Est. primary completion date: June 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 18 Years

Eligibility

Inclusion Criteria:

1. Considered reliable and willing to be available for the study duration and was able to record seizures and report adverse events (AEs) themselves or had a legal guardian or a caregiver who could record seizures and report AEs for them.

2. Understand the requirements of the Cognitive Drug Research (CDR) System tests and able to perform the tests appropriately at Visit 1.

3. Male or female, 12 to less than 18 years of age at the time of consent/assent

4. Had a diagnosis of epilepsy with partial-onset seizures with or without secondarily generalized seizures according to the International League Against Epilepsy's (ILAE) Classification of Epileptic Seizures (1981).

5. Diagnosis was established at least 6 months prior to Visit 1, by clinical history and an electroencephalogram (EEG) that was consistent with localization-related epilepsy; normal interictal EEGs were allowed provided that the subject met the other diagnosis criterion (ie, clinical history).

6. Had a brain imaging (e.g., magnetic resonance imaging [MRI] scan or computed tomography [CT]) within the 5 years prior to Visit 1 that ruled out a progressive cause of epilepsy.

7. Had at least 1 partial-onset seizure during the 4 weeks prior to Visit 1 despite a stable regimen of 1 to 3 concomitant antiepileptic drugs (AEDs).

8. Were currently being treated with stable doses of 1-3 AEDs. Only 1 inducer AED (either carbamazepine or phenytoin) out of the maximum of 3 AEDs was allowed.

9. Were on a stable dose of the same concomitant AED(s) for at least 4 weeks prior to Visit 1; in the case where a new AED regimen was initiated for a subject, the dose must have been stable for at least 8 weeks prior to Visit 1.

10. Female subjects of childbearing potential must had a negative serum human chorionic gonadotropin (beta-hCG) at Visit 1 and a negative urine pregnancy test prior to randomization at Visit 2. Female subjects of period of at least 60 days following administration of the last dose of study medication to 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]). Abstinence was considered an acceptable method of contraception on a case by case basis upon prior approval by the Medical Monitor.

11. Had an intelligence quotient (IQ) of greater than or equal to 70, using the Kaufman Brief Intelligence Test, second edition (KBIT-2).

12. Provided written informed consent signed by the legal guardian and a written assent from the subject prior to entering the study or undergoing any study procedures.

Extension Phase:

Had completed all scheduled visits up to and including Visit 8 in the Core Study Randomization Phase.

Exclusion Criteria:

1. Had a diagnosis of primary generalized epilepsies or seizures such as absences and/or myoclonic epilepsies.

2. Had current or a history of pseudo-seizures (psychogenic non-epileptic seizures [PNES]) within approximately 5 years prior to Visit 1.

3. Had a diagnosis of Lennox-Gastaut syndrome.

4. Had seizure clusters where individual seizures could not be counted.

5. Had a history of status epilepticus that required hospitalization during the 12 months prior to the Visit 1.

6. Had an unstable psychiatric diagnosis that could confound the investigator's ability to conduct the study or that could prevent completion of the protocol specified tests (e.g., significant suicide risk, including suicidal behavior and ideation 6 months prior to Visit 1, current psychotic disorder, or acute mania).

7. Had any concomitant illnesses/co-morbidities (e.g., autism, attention deficit hyperactivity disorder [ADHD]) at Visit 1 that could severely affect cognitive function during the course of the study.

8. Had previously participated in a clinical trial involving perampanel.

9. Had chronically or routinely use benzodiazepines and who have not discontinued the use at least 4 weeks prior to Visit 1.

Related Conditions & MeSH terms

• Epilepsy

Intervention

Drug:
• Perampanel
2 mg titrated up to 8-12 mg maximum; taken once daily.
• Placebo
Matching Placebo taken once daily.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Eisai Inc.

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Czechia,  Hungary,  India,  Korea, Republic of,  Latvia,  Poland,  Spain,  Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline to Week 19 in Cognition Drug Research (CDR) System Global Cognition Score (Core Study)	The CDR System Global Cognitive score was derived from the average of 5 CDR System cognitive domain scores (Power of Attention, Continuity of Attention, Quality of Episodic Memory, Quality of Working Memory, and Speed of Memory). The domain scores were normalized to mean of 50 and standard deviation of 10 before taking the average. The scale ranged from 0 - 100. An increase in the Global Cognitive Score indicates improvement, while a decrease indicates worsening in cognitive function.	Baseline (Visit 2/Week 0 Evaluation) and Week 19 LOCF (last observation carried forward)
Secondary	Change From Baseline at Week 19 in the Power of Attention T-score in the Randomization Phase (Core Study)	The Power of Attention domain (one of the 5 CDR System cognitive domains) was a measure of focused attention and information processing, comprised of the 3 CDR System attention tasks: the simple reaction time, choice reaction time and digit vigilance tasks. Z-scores were calculated for each domain by subtracting each participant's domain score from the normative population mean of that domain and dividing the result by the standard deviation (SD) of the normative population mean. Z-scores were converted into T-scores by multiplying by 50 and adding 50. Power of Attention were also multiplied by -1, so that for all domains, greater T-scores reflected superior cognitive function. T-scores ranged from 0 to 100, with a mean of 50 and an SD of 10. The CDR System Global Cognition score was created by adding the T-scores for the five domains. A decrease in the score of Power of Attention indicated improvement in cognitive function and a negative change reflects impairment from baseline.	Baseline and Week 19
Secondary	Change From Baseline at Week 19 in the Continuity of Attention T-score in the Randomization Phase (Core Study)	The Continuity of Attention domain (one of the 5 CDR System cognitive domains) was a measure of sustained attention, comprised of the accuracy scores from 2 of the CDR System attention tasks: choice reaction time and digit vigilance. Z-scores were calculated for this domain using normative data from the CDR System database for the age range of the study population. Specifically, Z-scores were calculated by subtracting each participant's domain score from the normative population mean of that domain and dividing the result by the SD of the normative population mean. Z-scores were converted into T-scores by multiplying by 50 and adding 50. Greater T-scores reflected superior cognitive function and a negative change from baseline reflects impairment compared to baseline. T-scores ranged from 0 to 100, with a mean of 50 and an SD of 10.	Baseline and Week 19
Secondary	Change From Baseline at Week 19 in the Quality of Episodic Secondary Memory T-score in the Randomization Phase (Core Study)	The Quality of Episodic Secondary Memory domain was a measure of the capability of individuals to encode, store, and subsequently retrieve verbal and nonverbal information in episodic (or declarative) memory; what was meant by memory in everyday terminology. This measure was derived by summing the scores from the 4 tasks: immediate and delayed word recall, word recognition, and picture recognition. Z-scores were calculated by subtracting each participant's domain score from the normative population mean of that domain and dividing the result by the SD of the normative population mean. Z-scores were converted into T-scores by multiplying by 50 and adding 50. Greater T-scores reflected superior cognitive function. T-scores ranged from 0 to 100, with a mean of 50 and an SD of 10. A high score reflects a good ability to store, hold and retrieve information of an episodic nature (i.e. an event or a name) and a negative change from baseline reflects impairment compared to baseline.	Baseline and Week 19
Secondary	Change From Baseline at Week 19 in the Quality of Working Memory (Short Term) T-score in the Randomization Phase (Core Study)	The Quality of Working Memory domain (one of the 5 CDR System cognitive domains) was a measure of reflecting how well individuals can hold numeric and spatial information 'on line' in working memory. Z-scores were calculated by subtracting each participant's domain score from the normative population mean of that domain and dividing the result by the SD of the normative population mean. Z-scores were converted into T-scores by multiplying by 50 and adding 50. Greater T-scores reflected superior cognitive function. T-scores ranged from 0 to 100, with a mean of 50 and an SD of 10. A higher score reflects a good working memory and a negative change from baseline reflects impairment compared to the baseline assessment.	Baseline and Week 19
Secondary	Change From Baseline at Week 19 in the Speed of Memory T-score in the Randomization Phase (Core Study)	The Speed of Memory domain (one of the 5 CDR System cognitive domains) was a measure, which reflects the time taken to accurately retrieve information from working and episodic memory. Z-scores were calculated for this domain using normative data from the CDR System database for the age range of the study population. Specifically, Z-scores were calculated by subtracting each participant's domain score from the normative population mean of that domain and dividing the result by the SD of the normative population mean. Z-scores were converted into T-scores by multiplying by 50 and adding 50. Speed of Memory were also multiplied by -1, so that for all domains, greater T-scores reflected superior cognitive function and a negative change from baseline reflects impairment compared to the baseline assessment. T-scores ranged from 0 to 100, with a mean of 50 and an SD of 10.	Baseline and Week 19
Secondary	Percentage of Participants Who Experienced 50% or More Decrease in Seizure Frequency (Core Study)	A responder was a participant who experienced a 50% or greater reduction in seizure frequency compared to the baseline of the Randomization Phase.	From Baseline up to Week 19 LOCF
Secondary	Percent Change From Baseline in Seizure Frequency Per 28 Days During the Treatment Duration of the Randomization Phase (Core Study)	Seizure frequency was based on overall number of seizures obtained by summing the 4 seizure types (all partial seizure types, that is, simple partial without motor signs, simple partial with motor signs, complex partial, and complex partial with secondary generalization) collected via the patient diary over a particular time interval and re-scaled to 28 days window.	Baseline and Week 19 LOCF
Secondary	Number of Participants Who Achieved Seizure-Free Status During the Maintenance Period and the Last 28 Days of the Maintenance Period During the Randomization Phase (Core Study)	Number of Participants who were seizure free, were assessed.	13 Week Maintenance Period
Secondary	Percent Change From Baseline in Seizure Frequency Per 28 Days Over the Perampanel Duration Exposure (Extension Phase)	The median percent change in total partial onset seizure frequency per 28 days during the Extension Phase relative to the Pre-perampanel Baseline from Week 1 of perampanel treatment through successive 13-week intervals (Weeks 1 to 13 for subjects with any data, Weeks 1 to 26 for subjects with exposure of more than 13 weeks, Weeks 1 to 39 for subjects with exposure of more than 26 weeks, and Week 1 to 52 for subjects with exposure of more than 52 weeks) are presented. The perampanel exposure duration starts from the first perampanel dose (in the Core Study for subjects previously randomized to perampanel or Extension Phase for subjects previously randomized to placebo) to the last perampanel dose in the Extension Phase.	Week 1-13, Week 14-26, Week 27-39, and Week 40-52
Secondary	Percentage of Participants Who Experienced 50% or More Decrease in Seizure Frequency Over the Perampanel Duration Exposure (Extension Phase)	A responder was a participant who experienced a 50% or greater reduction in seizure frequency per 28 days from pre-perampanel. The percentage of responders from Week 1 of perampanel treatment through successive 13-week intervals (Weeks 1 to 13 for subjects with any data, Weeks 1 to 26 for subjects with exposure of more than 13 weeks, Weeks 1 to 39 for subjects with exposure of more than 26 weeks, and Week 1 to 52 for subjects with exposure of more than 52 weeks) are presented. The perampanel exposure duration starts from the first perampanel dose (in the Core Study for subjects previously randomized to perampanel or Extension Phase for subjects previously randomized to placebo) to the last perampanel dose in the Extension Phase.	Week 1-13, Week 14-26, Week 27-39, and Week 40-52
Secondary	Mean Change From Baseline to End of Treatment in Cognition Drug Research (CDR) System Global Cognition Score (Extension Phase)	The CDR System Global Cognitive was derived from the average of 5 CDR System cognitive domain scores (Power of Attention, Continuity of Attention, Quality of Episodic Memory, Quality of Working Memory, and Speed of Memory). Domain scores were normalized to mean of 50 and standard deviation of 10 before taking the average. The scale ranged from 0 to 100. An increase in the Global Cognitive Score indicates improvement, while a decrease indicates worsening in cognitive function. The perampanel exposure duration starts from the first perampanel dose (in the Core Study for subjects previously randomized to perampanel or Extension Phase for subjects previously randomized to placebo) to the last perampanel dose in the Extension Phase.	Baseline, Week 9, Week 19, Week, 30, Week 39, Week 52, and End of Treatment (defined as the last nonmissing value after date of first perampanel dose up to 14 days after date of last dose)
Secondary	Mean Change From Baseline in CDR System Global Cognition Score Over Time (Extension Phase)	The CDR System Global Cognitive was derived from the average of 5 CDR System cognitive domain scores (Power of Attention, Continuity of Attention, Quality of Episodic Memory, Quality of Working Memory, and Speed of Memory). Domain scores were normalized to mean of 50 and SD of 10 before taking the average. The scale ranged from 0 to 100. An increase in the Global Cognitive Score indicates improvement, while a decrease indicates worsening in cognitive function. The data is presented as CDR System Global Cognitive scores at specific intervals (Week 9 for subjects with exposure of more than 9 weeks, Week 19 for subjects with exposure of more than 19 weeks, Week 30 for subjects with exposure of more than 26 weeks, Week 39 for subjects with exposure of more than 39 weeks, and Week 52 for subjects with exposure of more than 52 weeks).	Baseline, Week 9, Week 19, Week, 30, Week 39, and Week 52
Secondary	Mean Change From Baseline by Visits in CDR System Domain T-Scores (Extension Phase)	The Cognitive measure scores are presented as T-Scores. T-Scores were normalized standard scores with mean of 50 and SD of 10 with an absolute range of 0-100. The T-Scores are based on the norms from healthy age-matched controls from the CDR System database. Cohen's d-effect sizes were used to estimate the clinical relevance of a change in a parameter. A change in a score of 0.2 SD was defined by Cohen as a small effect size, 0.5 SD a medium effect size and 0.8 SD was considered a large effect size. An increase in the T-scores indicates improvement while a decrease in T-scores indicates worsening. Wk = Week and EOT=End of Treatment. The perampanel exposure duration starts from the first perampanel dose (in the Core Study for subjects previously randomized to perampanel or Extension Phase for subjects previously randomized to placebo) to the last perampanel dose in the Extension Phase.	Baseline, Week 9, Week 19, Week 30, Week 39, Week 52, and EOT (defined as the last nonmissing value after date of first dose up to 14 days after date of last dose)
Secondary	Mean Change From Baseline in CDR System Domain T-Score Over Time: Power of Attention (Extension Phase)	The Cognitive measure scores are presented as T-Scores at specific intervals (Week 9 for subjects with exposure of more than 9 weeks, Week 19 for subjects with exposure of more than 19 weeks, Week 30 for subjects with exposure of more than 26 weeks, Week 39 for subjects with exposure of more than 39 weeks, and Week 52 for subjects with exposure of more than 52 weeks). T-Scores were normalized standard scores with mean of 50 and SD of 10 with an absolute range of 0-100. The T-Scores are based on the norms from healthy age-matched controls from the CDR System database. Cohen's d-effect sizes were used to estimate the clinical relevance of a change in a parameter. A change in a score of 0.2 SD was defined by Cohen as a small effect size, 0.5 SD a medium effect size and 0.8 SD was considered a large effect size. An increase in the T-scores indicates improvement while a decrease in T-scores indicates worsening.	Baseline, Week 9, Week 19, Week 30, Week 39, and Week 52
Secondary	Mean Change From Baseline in CDR System Domain T-Score Over Time: Continuity of Attention (Extension Phase)	The Cognitive measure scores are presented as T-Scores at specific intervals (Week 9 for subjects with exposure of more than 9 weeks, Week 19 for subjects with exposure of more than 19 weeks, Week 30 for subjects with exposure of more than 26 weeks, Week 39 for subjects with exposure of more than 39 weeks, and Week 52 for subjects with exposure of more than 52 weeks). T-Scores were normalized standard scores with mean of 50 and SD of 10 with an absolute range of 0-100. The T-Scores are based on the norms from healthy age-matched controls from the CDR System database. Cohen's d-effect sizes were used to estimate the clinical relevance of a change in a parameter. A change in a score of 0.2 SD was defined by Cohen as a small effect size, 0.5 SD a medium effect size and 0.8 SD was considered a large effect size. An increase in the T-scores indicates improvement while a decrease in T-scores indicates worsening.	Baseline, Week 9, Week 19, Week, 30, Week 39, and Week 52
Secondary	Mean Change From Baseline in CDR System Domain T-Score Over Time: Quality of Episodic Secondary Memory (Extension Phase)	The Cognitive measure scores are presented as T-Scores at specific intervals (Week 9 for subjects with exposure of more than 9 weeks, Week 19 for subjects with exposure of more than 19 weeks, Week 30 for subjects with exposure of more than 26 weeks, Week 39 for subjects with exposure of more than 39 weeks, and Week 52 for subjects with exposure of more than 52 weeks). T-Scores were normalized standard scores with mean of 50 and SD of 10 with an absolute range of 0-100. The T-Scores are based on the norms from healthy age-matched controls from the CDR System database. Cohen's d-effect sizes were used to estimate the clinical relevance of a change in a parameter. A change in a score of 0.2 SD was defined by Cohen as a small effect size, 0.5 SD a medium effect size and 0.8 SD was considered a large effect size. An increase in the T-scores indicates improvement while a decrease in T-scores indicates worsening.	Baseline, Week 9, Week 19, Week 30, Week 39, and Week 52
Secondary	Mean Change From Baseline in CDR System Domain T-Score Over Time: Quality of Working Memory (Short Term) (Extension Phase)	The cognitive measure scores are presented as T-Scores at specific intervals (Week 9 for participants with exposure of more than 9 weeks, Week 19 for participants with exposure of more than 19 weeks, Week 30 for participants with exposure of more than 26 weeks, Week 39 for participants with exposure of more than 39 weeks, and Week 52 for participants with exposure of more than 52 weeks). T-Scores were normalized standard scores with mean of 50 and SD of 10 with an absolute range of 0-100. The T-Scores are based on the norms from healthy age-matched controls from the CDR System database. Cohen's d-effect sizes were used to estimate the clinical relevance of a change in a parameter. A change in a score of 0.2 SD was defined by Cohen as a small effect size, 0.5 SD a medium effect size and 0.8 SD was considered a large effect size. An increase in the T-scores indicates improvement while a decrease in T-scores indicates worsening.	Baseline, Week 9, Week 19, Week, 30, Week 39, and Week 52
Secondary	Mean Change From Baseline in CDR System Domain T-Score Over Time: Speed of Memory (Extension Phase)	The Cognitive measure scores are presented as T-Scores at specific intervals (Week 9 for subjects with exposure of more than 9 weeks, Week 19 for subjects with exposure of more than 19 weeks, Week 30 for subjects with exposure of more than 26 weeks, Week 39 for subjects with exposure of more than 39 weeks, and Week 52 for subjects with exposure of more than 52 weeks). T-Scores were normalized standard scores with mean of 50 and SD of 10 with an absolute range of 0-100. The T-Scores are based on the norms from healthy age-matched controls from the CDR System database. Cohen's d-effect sizes were used to estimate the clinical relevance of a change in a parameter. A change in a score of 0.2 SD was defined by Cohen as a small effect size, 0.5 SD a medium effect size and 0.8 SD was considered a large effect size. An increase in the T-scores indicates improvement while a decrease in T-scores indicates worsening.	Baseline, Week 9, Week 19, Week, 30, Week 39, and Week 52
Secondary	Change From Baseline to End of Treatment in Controlled Oral Word Association Test Scores (COWAT) (Extension Phase)	The COWAT test measured the executive function of the frontal lobe and consisted of examinations of category/meaning fluency and letter/phoneme fluency. It consisted of 2 parts which included the Letter Fluency task and the Category Fluency task. For the Letter Fluency task, the participant was given one minute to list as many words as they could which began with a given letter from the following set of 3 letters: F, A, and L. The number of correct words from the 3 sets comprised the Letter Fluency score. For the Category Fluency task, the participant was given one minute to list as many words as they could which belonged to a given category. The number of correct words comprised the Category Fluency score. Total score was calculated as sum of acceptable words generated. The scale ranged from 0-90, with higher scores indicating improvement in language.	From Baseline up to Week 52 or up to EOT (defined as the last nonmissing value after date of first dose up to 14 days after date of last dose)
Secondary	Change From Baseline to End of Treatment in Time to Complete Lafayette Grooved Pegboard Test (LGPT) (Extension Phase)	The LGPT test measured visuomotor skills. This test was a manipulative dexterity test that consisted of a metal matrix of 25 holes with randomly positioned slots. The participant was required to insert 25 grooved pegs into the holes. The task was completed once for each hand; firstly, using the dominant hand followed by the non-dominant hand. The task was timed and the scores were the time taken for the participant to complete all 25 pegs for each hand. If the test cannot be completed within 300 seconds, 300 seconds were recorded for the time. An increase in score (longer time) indicated worsening of visuomotor skills. The time to complete test is presented as mean seconds +/- SD.	From Baseline up to Week 52 or up to EOT (defined as the last nonmissing value after date of first dose up to 14 days after date of last dose)
Secondary	Mean Change From Baseline in Bone Age Minus Age (Months) From Hand X-ray (Extension Phase)	Bone age was measured using hand X-ray. The mean change from Baseline in bone age (months) minus age (months) from the hand x-ray was assessed. "+" means bone age is older than age and "-" means bone age is younger than age.	From Baseline up to Week 52 or up to EOT (defined as the last nonmissing value after date of first dose up to 14 days after date of last dose)
Secondary	Change From Baseline to End of Treatment (EOT) for the Tanner Stage	The effect of perampanel on growth and development in adolescents (male and female), including sexual development was measured using Tanner scale. The scale defined physical measurements of development based on external primary and secondary sex characteristics, such as the size of the breasts, genitals, testicular volume and development of pubic hair. Tanner scale consisted of 5 scales from I to V (1: pre-pubertal to 5: adult). Data is reported as the change from Baseline to End of Treatment for the Tanner Stage.	From Baseline up to Week 52 or EOT (defined as the last nonmissing value after date of first dose up to 14 days after date of last dose)