Trial Outcomes & Findings for A Study With an Open-label Extension Phase to Evaluate the Effect of Perampanel (E2007) on Cognition, Growth, Safety, Tolerability, and Pharmacokinetics in Adolescents (NCT NCT01161524)

Of the 154 participants screened for entry into the Core Study, 21 were screen failures and 133 were randomized and treated. A total of 119 participants completed the Core Study, and 114 participants entered the Extension Phase.

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

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.

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.

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.

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.

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.

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.

A responder was a participant who experienced a 50% or greater reduction in seizure frequency compared to the baseline of the Randomization Phase.

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.

Number of Participants who were seizure free, were assessed.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.