Perampanel as Adjunctive Therapy in Pediatrics With Partial Onset Seizures or Primary Generalized Tonic Clonic Seizures

Seizure frequency derived from information (seizure count and type) recorded in participant diary. Seizure frequency per 28 days was calculated as number of seizures divided by number of days in interval; multiplied by 28. Due to sparse pharmacokinetic (PK) sampling in study, data of endpoint was analyzed by pooling data from other Phase II and III studies of perampanel along with data of this current study, including participants with POS or PGTC. Only data for participants taking perampanel 8 mg/day (corresponding to Cav, ss of 518 ng/mL) were reported. Participants taking perampanel 12 mg/day in studies from which data were pooled, were not included in analysis for this measure. Here, ng/mL= nanogram per milliliter. Data for this measure was calculated through model prediction; reported as "percent change" with measure type as "number" and measure dispersion as "Not applicable, NA".

For this outcome measure, responders were those who experienced a 50 percent (%) or greater reduction in seizure frequency per 28 days from baseline. Due to the sparse PK sampling in this study, the data of this outcome measure were pooled with data from other Phase III studies of perampanel conducted in participants with POS. "AEDs not affecting PK" refers to AEDs not affecting PK of perampanel. Data for this outcome measure has been reported for only non-Asian participants with POS per age groups. Responder probability has been reported for Cav,ss of perampanel when given along with different antiepileptic drugs (AEDs).

For this outcome measure, responders were those who experienced a 50% or greater reduction in seizure frequency per 28 days from baseline. Due to the sparse PK sampling in this study, the data of this outcome measure were analyzed by pooling the data from other Phase II and III studies of perampanel along with data of this current study, including participants with PGTC seizures. In this outcome measure, responder probability at different concentration values of perampanel when given with or without topiramate (an antiepileptic) has been reported.

Due to the sparse PK sampling in this study, the data of this outcome measure were analyzed by pooling data from other Phase II and III studies of perampanel along with this current study, including participants with POS or PGTC. Data for this outcome measure have been reported in relationship with different ranges of Cav, ss of Perampanel as "number of observations" those were seizure free for up to 3 visits. The reason for using number of observations for analysis of this outcome measure was because data were available as up to 3 visits per participant and not necessarily that the participant was seizure-free on all three visits.

The ABNAS assessment measured 5 aspects of cognitive function such as fatigue, memory, concentration, motor speed, and reading. The assessment was a measure of participant-perceived cognitive effects of AEDs. This instrument was aimed at assessing participant perceived drug-related cognitive impairment. Total score ranged from 0-72. Higher scores indicate a worsening of these cognitive functions. Analysis for this outcome measure was planned to be performed via Pharmacokinetic/Pharmacodynamic (PK/PD) modelling only if a graphical relationship between perampanel exposure and change from baseline in ABNAS could be discerned.

The CBCL for participants with age 4 to 5 years is a questionnaire to assess behavioral and emotional problems in children as reported by the primary caregiver for the following domains activities: emotionally reactive, anxious/depressed, withdrawn, somatic complaints, internalizing, attention problems, aggressive behavior, externalizing, sleep problems. CBCL total score for participants with age 4 to 5 years ranged from 0 to 200, was calculated by adding individual score of each domain. Higher scores indicate greater problems in child behavior. Analysis for this outcome measure was planned to be performed via PK/PD modelling only if a graphical relationship between perampanel exposure and change from baseline in CBCL score (participants aged 4 to 5 years) could be discerned.

The CBCL for participants with age >5 to <12 years is a questionnaire to assess behavioral and emotional problems in children as reported by the primary caregiver for the following domains activities: activity, social, school, total competence, anxious/depressed, withdrawn/depressed, somatic complaints, internalizing, rule-breaking behavior, aggressive behavior, externalizing, social problems, thought problems, attention problems. CBCL total score for participants with age >5 to <12 years ranged from 0 to 240, was calculated by adding individual score of each domain. Higher scores indicate greater problems in child behavior. Analysis for this outcome measure was planned to be performed via PK/PD modelling only if a graphical relationship between perampanel exposure and change from baseline in CBCL score (participants aged >5 to <12 years) could be discerned.

The Lafayette Grooved Pegboard Test (LGPT) measures visuomotor skills. This test is a manipulative dexterity test that consist of a metal matrix of 25 holes with randomly positioned slots. Participants require to insert 10 grooved pegs into the holes. The task needs to be completed once for each hand; firstly, using the dominant hand followed by the non-dominant hand. The task is timed and the scores are the time taken for the participant to complete all 10 pegs for each hand. If the test cannot be completed within 300 seconds, 300 seconds are recorded for the time. An increase in score (longer time) indicate worsening of visuomotor skills. Analysis for this outcome measure was planned to be performed via PK/PD modelling only if a graphical relationship between perampanel exposure and change from baseline in Total Time to Complete LGPT Score for Dominant Hand could be discerned.

The Lafayette Grooved Pegboard Test (LGPT) measures visuomotor skills. This test is a manipulative dexterity test that consist of a metal matrix of 25 holes with randomly positioned slots. Participants require to insert 10 grooved pegs into the holes. The task needs to be completed once for each hand; firstly, using the dominant hand followed by the non-dominant hand. The task is timed and the scores are the time taken for the participant to complete all 10 pegs for each hand. If the test cannot be completed within 300 seconds, 300 seconds are recorded for the time. An increase in score (longer time) indicate worsening of visuomotor skills. Analysis for this outcome measure was planned to be performed via PK/PD modelling only if a graphical relationship between perampanel exposure and change from baseline in Total Time to Complete LGPT Score for Non-dominant Hand could be discerned.

The ABNAS assessment measured 5 aspects of cognitive function such as fatigue, memory, concentration, motor speed, and reading. The assessment was a measure of participant-perceived cognitive effects of AEDs. This instrument was aimed at assessing participant perceived drug-related cognitive impairment. Total score ranged from 0-72. Higher scores indicate a worsening of these cognitive functions.

The CBCL for participants (age group 1.5 to 5 years) is a questionnaire to assess behavioral and emotional problems in children as reported by the primary caregiver for the following domains activities: emotionally reactive, anxious/depressed, withdrawn, somatic complaints, internalizing, attention problems, aggressive behavior, externalizing, sleep problems. CBCL total score for participants (age group 1.5 to 5 years) ranged from 0 to 200, was calculated by adding individual score of each domain. Higher scores indicate greater problems in child behavior.

The CBCL for participants (age group 6 to 18 years) is a questionnaire to assess behavioral and emotional problems in children as reported by the primary caregiver for the following domains activities: activity, social, school, total competence, anxious/depressed, withdrawn/depressed, somatic complaints, internalizing, rule-breaking behavior, aggressive behavior, externalizing, social problems, thought problems, attention problems. CBCL total score for participants (age group 6 to 18 years) ranged from 0 to 240, was calculated by adding individual score of each domain. Higher scores indicate greater problems in child behavior.

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 10 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 10 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 plus/minus (+/-) SD.

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.

Thyrotropin level was measured in milli-international units per liter (mIU/L).

C-SSRS: interview-based instrument to systematically assess suicidal ideation (SI) and behavior, to assess whether participant experienced any of following: completed suicide, suicide attempt (response of "yes" on "actual attempt"), preparatory acts toward imminent suicidal behavior ("yes" on "preparatory acts or behavior", "aborted attempt" or "interrupted attempt"), suicidal ideation ("yes" on "wish to be dead", "non-specific active suicidal thoughts", "active SI with methods without intent to act or some intent to act, without or with specific plan and intent), any self-injurious behavior with no suicidal intent ("yes" on "has participant engaged in non-suicidal self-injurious behavior").Here, percentage of participants with >=1 positive behavior, participants with >=1 positive ideations; suicidality were reported.An assessment of SI and behavior with C-SSRS performed for participants >=6 years at time of consent.

The C-SSRS: interview-based instrument to systematically assess suicidal ideation (SI) and suicidal behavior, to assess whether participant experienced any of the following: completed suicide, suicide attempt (response of "yes" on "actual attempt"), preparatory acts toward imminent suicidal behavior ("yes" on "preparatory acts or behavior", "aborted attempt" or "interrupted attempt"), suicidal ideation ("yes" on "wish to be dead", "non-specific active suicidal thoughts", "active SI with methods without intent to act or some intent to act, without specific plan or with specific plan and intent), any self-injurious behavior with no suicidal intent ("yes" on "has participant engaged in non-suicidal self-injurious behavior"). "w/" refers to "with", "W" refers to "Week" and "\&" refers to "and".

Seizure frequency was based on number of seizures per 28 days, calculated as number of seizures over entire time interval divided by number of days in interval and multiplied by 28. Total POS: sum of all POS including simple partial seizures without motor signs, simple partial seizures with motor signs, complex partial seizures, and complex partial seizures with secondary generalization (SG). Data for this measure has been reported for 13 week time periods as per age groups.

A 25% responder was a participant who experienced a 25% or greater reduction in seizure frequency per 28 days from baseline. Total POS: sum of all POS including simple partial seizures without motor signs, simple partial seizures with motor signs, complex partial seizures, and complex partial seizures with SG. Data for this outcome measure has been reported for 13 week time periods as per age groups.

A 50% responder was a participant who experienced a 50% or greater reduction in seizure frequency per 28 days from baseline. Total POS: sum of all POS including simple partial seizures without motor signs, simple partial seizures with motor signs, complex partial seizures, and complex partial seizures with SG. Data for this outcome measure has been reported for 13 week time periods as per age groups.

A 75% responder was a participant who experienced a 75% or greater reduction in seizure frequency per 28 days from baseline. Total POS: sum of all POS including simple partial seizures without motor signs, simple partial seizures with motor signs, complex partial seizures, and complex partial seizures with SG. Data for this outcome measure has been reported for 13 week time periods as per age groups.

Participants were considered seizure free if participants completed a 13-week time period and were seizure-free for that entire time period. Total POS: sum of all POS including simple partial seizures without motor signs, simple partial seizures with motor signs, complex partial seizures, and complex partial seizures with SG. Data for this outcome measure has been reported for 13 week time periods as per age groups.

Assessment of disease severity utilized the CGIC scale at end of treatment to evaluate participant's change in disease status from baseline. The CGIC is a 7-point scale that measures a physician's global impression of a participant's clinical condition. Scale ranged from 1 to 7 with lower score indicated improvement (1=very much improved, 2=much improved, 3=minimally improved), higher score indicated worsening (5=minimally worse, 6= much worse, 7=very much worse), and a score of 4 indicated no change.