Study of Perampanel as Adjunctive Treatment for Inadequately Controlled Seizures Associated With Lennox-Gastaut Syndrome

Study Overview
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Brief Summary
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This study is being conducted to demonstrate that perampanel given as adjunctive anti-epileptic treatment is superior to placebo in reducing the number of drop seizures in participants with inadequately controlled seizures associated with Lennox-Gastaut Syndrome (LGS).

Detailed Description
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This is a multicenter, double-blind, randomized, placebo-controlled, parallel-group study of perampanel as adjunctive therapy in participants with inadequately controlled seizures associated with LGS. The study will consist of 3 phases: Prerandomization (4 to 8 weeks), Randomization (18 weeks), and an Extension A (52 weeks). An additional Extension B with open-label treatment will be available for optional participation to participants who reside in Japan and in countries where an expanded access program (EAP) cannot be implemented or has not yet been implemented.

Official Title
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A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial With an Open-Label Extension Phase of Perampanel as Adjunctive Treatment in Subjects at Least 2 Years of Age With Inadequately Controlled Seizures Associated With Lennox-Gastaut Syndrome

Conditions
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Lennox-Gastaut Syndrome (LGS)

Intervention / Treatment
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* Drug: Placebo
* Drug: Perampanel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have a diagnosis of LGS as evidenced by: more than one type of generalized seizure, including drop seizures (atonic, tonic, or myoclonic) for at least 6 months before Visit 1; an electroencephalogram (EEG) reporting diagnostic criteria for LGS at some point in their history (abnormal background activity accompanied by slow, spike, and wave pattern <2.5 hertz [Hz]). Participants must be at least 2 years old at the time of consent/assent Participants must have been <11 years old at the onset of LGS Participants must have experienced an average of at least 2 drop seizures per week in the 4-week Baseline Period preceding randomization Participants must have been receiving 1 to 4 concomitant antiepileptic drugs (AEDs) at a stable dose for at least 30 days before Visit 1 (vagal nerve stimulation (VNS) and ketogenic diet do not count as AEDs). Use of cannabidiol (CBD) products is allowed and is counted as one of the 4 maximum allowed concomitant AEDs. CBD dose and product must have remained stable for at least 30 days before Visit 1 and is to remain the same throughout the course of the Core Study In the investigator's opinion, parents or caregivers must be able to keep accurate seizure diaries Body weight at least 8 kilogram (kg) Exclusion Criteria: Presence of progressive neurological disease Presence of drop seizure clusters where individual seizures cannot be reliably counted (seizure clusters are defined as ≥2 drop seizures with <5 minutes between any 2 consecutive seizures) Prior treatment with perampanel with discontinuation due to safety issues (related to perampanel) Prior treatment with perampanel within 30 days before Visit 1 Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal disease, hepatic disease) that in the opinion of the investigator(s) could affect the participant's safety or study conduct Scheduled for epilepsy-related surgery or any other form of surgery during the projected course of the study Ketogenic diet and VNS, unless stable and ongoing for at least 30 days before Visit 1 Treatment with an investigational drug or device within 30 days before Visit 1 Status epilepticus within 12 weeks of Visit 1 If felbamate is used as a concomitant AED, participants must be on felbamate for at least 1 year, with a stable dose for 60 days before Visit 1. They must not have a history of white blood cell (WBC) count below ≤2500/microliters (μL), platelets <100,000/μL, liver function tests (LFTs) >3 times the upper limit of normal (ULN), or other indication of hepatic or bone marrow dysfunction while receiving felbamate Concomitant use of vigabatrin: participants who took vigabatrin in the past must be discontinued for at least 5 months before Visit 1, and must have documentation showing no evidence of a vigabatrin-associated clinically significant abnormality in an automated visual perimetry test Have had multiple drug allergies or a severe drug reaction to an AED(s), including dermatological (eg, Stevens-Johnson syndrome), hematological, or organ toxicity reactions Evidence of significant active hepatic disease. Stable elevations of liver enzymes, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) due to concomitant medication(s) will be allowed if they are < 3 times the ULN Adrenocorticotropic hormone within the 6 months before Visit 1 Had history of anoxic episodes requiring resuscitation within 6 months before Visit 1 Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta human chorionic gonadotropin [ß-hCG] with a minimum sensitivity of 25 International Units per Liter (IU/L) or equivalent units of ß-hCG or hCG). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug. Females of childbearing potential who: a. had unprotected sexual intercourse within 30 days before study entry and who do not agree to use a highly effective method of contraception (eg, total abstinence, an intrauterine device, a double-barrier method [such as condom plus diaphragm with spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period or for 28 days after study drug discontinuation. Females using hormonal contraceptives containing levogesterol must be on another form of contraception as well. b. Are currently abstinent, and do not agree to use a double-barrier method (as described above) or refrain from sexual activity during the study period or for 28 days after study drug discontinuation. c. Are using hormonal contraceptives but are not on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and who do not agree to use the same contraceptive during the study or for 28 days after study drug discontinuation. (NOTE: All females will be considered to be of childbearing potential unless they are postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause] or have been sterilized surgically [i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing]) Had intermittent use of benzodiazepine of more than 4 single administrations in the month before Visit 1 A prolonged QT/QTc interval (QTc >450 milliseconds [ms]) as demonstrated by a repeated electrocardiogram (ECG) Hypersensitivity to the study drug or any of the excipients Any history of a medical condition or a concomitant medical condition that in the opinion of the investigator(s) would compromise the participant's ability to safely complete the study Known to be human immunodeficiency virus (HIV) positive Active viral hepatitis (B or C) as demonstrated by positive serology at Screening Psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of antipsychotics or prior suicide attempt(s) within approximately the last 2 years History of drug or alcohol dependency or abuse within approximately the last 2 years; use of illegal recreational drugs Concomitant use of medications known to be inducers of cytochrome P450 (CYP3A) including, but not limited to: rifampin, troglitazone, St. John's Wort, efavirenz, nevirapine, glucocorticoids (other than topical usage), modafinil, pioglitazone, and rifabutin Use of AEDs not recommended by Epilepsy Treatment Guidelines for use in LGS including, but not limited to carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine, and vigabatrin Any suicidal ideation with intent with or without a plan within 6 months before Visit 2 (that is, answering Yes to questions 4 or 5 on the Suicidal Ideation section of the Columbia Suicide Severity Rating Scale (C -SSRS) in participants aged 8 and above. Participants with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Perampanel up to 8 mg/day<br>During the Randomization Phase, participants will receive perampanel at a starting dose of 2 milligrams per day (mg/day). Thereafter, the dose will be increased to a maximum target dose of 8 mg/day according to individual tolerability and efficacy for up to 18 weeks. Participants who enter into Extension A will continue to receive perampanel at the dose last received during randomization phase. Participants can be titrated up to 12 mg/day (at 2-week intervals) per the investigator's discretion. Participants who continue in Extension B will continue to receive perampanel at the dose last received at the end of Extension A. | Drug: Perampanel<br>* Participants will receive perampanel in Randomization phase, open-label Extension A, and open-label Extension B.<br>* Other names: E2007;|
| Placebo Comparator: Matching placebo<br>During the Randomization Phase, participants will receive matching placebo for up to 18 weeks. During the Extension A, participants who received placebo during the Randomization Phase will begin treatment with perampanel in a blinded manner in double-blind Conversion Period, starting at 2 mg/day and then up-titrated to a maximum target dose of 8 mg/day according to individual tolerability and efficacy. After the Conversion Period, participants can be titrated up to 12 mg/day (at 2-week intervals) per the investigator's discretion. | Drug: Placebo<br>* Participants will receive matching placebo in Randomization phase.<br>Drug: Perampanel<br>* Participants will receive perampanel in Randomization phase, open-label Extension A, and open-label Extension B.<br>* Other names: E2007;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core Study Phase: Median Percent Change in Drop Seizure Frequency Per 28 Days During Double-blind Treatment Relative to the Prerandomization Phase (Baseline) | Drop seizure was defined as a drop attack or spell involving the entire body, trunk, or head that led to a fall, injury, slumping in a chair, or the participant's head hitting a surface or that could have led to a fall or injury, depending on the participant's position at the time of the attack or spell. Seizure frequency was based on the number of drop seizures per 28 days, calculated as the number of drop seizures over the entire time interval divided by the number of days in the interval and multiplied by 28. | Baseline up to 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core Study Phase: Median Percent Change in Total Seizure Frequency Per 28 Days During Double-blind Treatment Relative to the Prerandomization Phase (Baseline) | Total seizure was the number of seizures assessed and recorded by the participant's parent/caregiver in the participant seizure diary. Seizure diaries were used to collect seizure counts and types. Seizure frequency was based on the number of drop seizures per 28 days, calculated as the number of drop seizures over the entire time interval divided by the number of days in the interval and multiplied by 28. | Baseline up to 18 weeks | 
| Core Study Phase: Percentage of Participants With 50% Response in the Maintenance Period of the Double-blind Treatment Phase Relative to the Prerandomization Phase (Baseline) for Drop Seizures | Drop seizure was defined as a drop attack or spell involving the entire body, trunk, or head that led to a fall, injury, slumping in a chair, or the participant's head hitting a surface or that could have led to a fall or injury, depending on the participant's position at the time of the attack or spell. A responder was a participant who experienced a 50% or greater reduction in drop seizure frequency per 28 days during Maintenance from prerandomization. | Baseline up to 18 weeks | 
| Core Study Phase: Percentage of Participants With 50% Response in the Maintenance Period of the Double-blind Treatment Phase Relative to the Prerandomization Phase (Baseline) for Total Seizures | Total seizure was the number of seizures assessed and recorded by the participant's parent/caregiver in the participant seizure diary. Seizure diaries was used to collect seizure counts and types. A responder was a participant who experienced a 50% or greater reduction in drop seizure frequency per 28 days during Maintenance from prerandomization. | Baseline up to 18 weeks | 
| Core Study Phase: Median Percent Change in Non-drop Seizure Frequency Per 28 Days During Double-blind Treatment Phase Relative to the Prerandomization Phase (Baseline) | Non-drop seizures were defined as non-drop attacks or spells. Drop attacks and spells involved the entire body, trunk, or head and lead to a fall, injury, slumping in a chair, or the participant's head hitting a surface, or could lead to a fall or injury, depending on the participant's position at the time of the attack or spell. Seizure frequency was based on the number of drop seizures per 28 days, calculated as the number of drop seizures over the entire time interval divided by the number of days in the interval and multiplied by 28. | Baseline up to 18 weeks | 
| Core Study Phase: Percentage of Participants With 75% Response in the Maintenance Period of the Double-blind Treatment Phase Relative to the Prerandomization Phase (Baseline) for Drop Seizures, Non-drop Seizures and Total Seizures | Drop seizure was defined as a drop attack or spell involving the entire body, trunk, or head that led to a fall, injury, slumping in a chair, or the participant's head hitting a surface or that could have led to a fall or injury, depending on the participant's position at the time of the attack or spell. Non-drop seizures were defined as non-drop attacks or spells. Total seizure was the number of seizures assessed and recorded by the participant's parent/caregiver in the participant seizure diary. Seizure diaries were used to collect seizure counts and types. A responder was a participant who experienced a 75% or greater reduction in drop seizure/non-drop seizure/ frequency per 28 days during Maintenance from prerandomization. | Baseline up to 18 weeks | 
| Core Study Phase: Percentage of Participants With 100% Response in the Maintenance Period of the Double-blind Treatment Phase Relative to the Prerandomization Phase (Baseline) for Drop Seizures, Non-drop Seizures and Total Seizures | Drop seizure was defined as a drop attack or spell involving the entire body, trunk, or head that led to a fall, injury, slumping in a chair, or the participant's head hitting a surface or that could have led to a fall or injury, depending on the participant's position at the time of the attack or spell. Non-drop seizures were defined as non-drop attacks or spells. Total seizure was the number of seizures assessed and recorded by the participant's parent/caregiver in the participant seizure diary. Seizure diaries was used to collect seizure counts and types. A responder was a participant who experienced a 100% or greater reduction in drop seizure/non-drop seizure/ frequency per 28 days during Maintenance from prerandomization. | Baseline up to 18 weeks | 
| Core Study Phase: Percentage of Participants With 50% Response in the Maintenance Period of the Double-blind Treatment Phase Relative to the Prerandomization Phase (Baseline) for Non-drop Seizures | Non-drop seizures were defined as non-drop attacks or spells. Drop attacks and spells involved the entire body, trunk, or head and lead to a fall, injury, slumping in a chair, or the participant's head hitting a surface, or could lead to a fall or injury, depending on the participant's position at the time of the attack or spell. A responder was a participant who experienced a 50% or greater reduction in non-drop seizure frequency per 28 days during Maintenance from prerandomization. | Baseline up to 18 weeks | 
| Core Study Phase: Percentage of Participants With Clinical Global Impression of Change Scores (CGIC) in the Double-blind Treatment Phase | Assessment of disease severity utilized the CGIC scale at end of treatment to evaluate participants change in disease status from baseline. The CGIC is a 7-point likert scale that measures a physician's global impression of a participants 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. | Baseline up to 18 weeks | 
| Number of Participants With Any Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | A TEAE was defined as an adverse event with an onset date, or a worsening in severity from baseline (pre-treatment), on or after the first dose of study drug up to 28 days following study drug discontinuation. An AE was defined as any untoward medical occurrence in a participant or clinical investigation in a participant administered an investigational product. An AE does not necessarily have a causal relationship with a medicinal product. A serious adverse event (SAE) was defined as any AE if it resulted in death or life-threatening AE or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions or was a congenital anomaly/birth defect. | From the date of the first administration of the study drug up to 28 days after the last dose of the study drug (up to 192 weeks) | 
| Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values | Treatment-emergent markedly abnormal value for laboratory values was based Common Terminology Criteria for Adverse events (CTCAE) Version 4.0, and determined as if the post baseline CTCAE Version 4.0 grade increases from baseline and the post baseline grade was >=2 (>=3 for phosphate). Laboratory tests included: Hematology count with differential, Chemistry (Electrolytes, Liver function tests, Renal function parameters, Other: albumin, calcium, cholesterol, globulin, glucose, lactate dehydrogenase, phosphorus, total protein, lipid panel, uric acid), Urinalysis, and Viral tests (Hepatitis B surface antigen, Hepatitis C). | From the date of the first administration of the study drug up to 28 days after the last dose of the study drug (up to 192 weeks) | 
| Number of Participants With Clinically Significant Vital Signs | Clinically significant means that a value must have met both the criterion value and satisfied the magnitude of change relative to baseline. Vital sign parameters included systolic blood pressure (BP), diastolic BP, pulse rate. | From the date of the first administration of the study drug up to 28 days after the last dose of the study drug (up to 192 weeks) | 
| Core Study Phase: Model Predicted Average Perampanel Concentrations at Steady State (Cav,ss) During the Maintenance Period of Core Study Phase | Due to the early termination of the study resulting in reduced sample size and the variability in treatment response, population pharmacokinetic (PK) analysis and population pharmacokinetic/pharmacodynamic (PK/PD) modeling planned for this study were not conducted and hence data was not collected and analyzed for this outcome measure. | Up to Week 18 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lennox-Gastaut Syndrome (LGS), Inadequately controlled seizures