Investigate Efficacy and Safety of Carisbamate as Adjunctive Treatment for Seizures Associated With LGS in Children and Adults

Study Overview
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Brief Summary
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The primary objective is to evaluate the efficacy of carisbamate (YKP509) as adjunctive treatment in reducing the number of drop seizures (tonic, atonic, and tonic-clonic) compared with placebo in pediatric and adult subjects (age 4-55 years) diagnosed with Lennox Gastaut Syndrome (LGS).

Detailed Description
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The secondary objectives are: To evaluate the efficacy of carisbamate (YKP509) as adjunctive treatment in reducing the total number of seizures compared with placebo in pediatric and adult subjects diagnosed with Lennox Gastaut Syndrome (LGS) Assess subject's Quality of Life (QOL) Evaluate the safety, tolerability of carisbamate in the LGS population Evaluate steady-state pharmacokinetics of carisbamate in subjects with Lennox Gastaut.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy and Safety of Carisbamate (YKP509) as Adjunctive Treatment for Seizures Associated With Lennox-Gastaut Syndrome in Children and Adults, With Optional Open-Label Extension

Conditions
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Seizures, Lennox Gastaut Syndrome

Intervention / Treatment
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* Drug: Carisbamate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must have a documented history of Lennox-Gastaut syndrome by: Evidence of more than one type of seizure, of which at least one should be an atonic or tonic seizure History of an electroencephalogram (EEG) reporting diagnostic criteria for LGS (abnormal background activity accompanied by slow, spike and wave pattern <3.0 Hz) History of developmental delay Male or female subjects Subjects must be age 4-55 years at the time of consent/assent Must have been <11 years old at the onset of LGS Subjects must have experienced at least 2 drop seizures with potential to fall (tonic, atonic, tonic-clonic) each week during the 4-week Baseline period preceding randomization. Drop seizures are defined as a seizure involving the entire body, trunk, or head that led or could have led to a fall, injury, slumping in a chair, or hitting the subject's head on a surface. For seizures that occur in clusters: if countable, an exact seizure count should be used; if uncountable, the caregiver should estimate the number of seizures. Subjects must have been receiving 1 to 4 concomitant anti-seizure medications (ASMs) at a stable dose for at least 4 weeks before Visit 1 If not taking Epidiolex, subjects may take other approved cannabidiol or over the counter cannabidiol products. If taking cannabidiol other than Epidiolex, consult Medical Monitor to determine if it counts as a concomitant ASM. Dietary therapy and any CNS stimulator settings must be stable for 4 weeks prior to baseline and maintain stable regimen throughout the study. The dietary therapy and CNS stimulators are not counted as an ASM. Parents or caregivers must be able to keep accurate seizure diaries Subject is either not of childbearing potential, defined as premenarchal, postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), if of childbearing potential, must comply with an acceptable method of birth control during the study, for at least 4 weeks prior to study entry and for 4 weeks following completion of the study, if able. Subject and/or parent(s)/legal representative must be willing and able to give informed assent/consent for participation in the study Subject and their caregiver must be willing and able (in the investigator's opinion) to comply with all study requirements History of COVID-19 vaccination is permitted Exclusion Criteria: Etiology of subject's seizures is a progressive neurologic disease. Subjects with tuberous sclerosis will not be excluded from study participation, unless there is a progressive brain tumor Evidence of clinically significant disease (e.g., cardiac, respiratory, gastrointestinal, renal disease, hepatic disease) that in the opinion of the investigator(s) could affect the subject's safety or study conduct Subjects who were on adrenocorticotropic hormone (ACTH) therapy in the 6 months prior to baseline Subject on dietary therapy for less than 4 weeks prior to screening visit (Visit 1) or suffers from frequent stooling Current use of felbamate with less than 18 months of continuous exposure Concomitant use of vigabatrin: subjects 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, if able. Subject who had a history of hypoxia which needed emergency resuscitation within 12 months prior to baseline Status epilepticus within 12 weeks of Visit 1 Any clinically significant illness (including COVID-19) in the 4 weeks prior to Visit 1, as determined by the Investigator Subject has clinically significant abnormal laboratory values, in the investigator's opinion, at Visit 1 or time of randomization (Visit 2) Subject has a history of any serious drug-induced hypersensitivity, e.g., toxic epidermal necrolysis, or Drug Reaction with Eosinophilia and Systemic Symptoms [DRESS]) or any drug-related rash requiring hospitalization Vagus Nerve Stimulation (VNS), Deep Brain Stimulation (DBS), Responsive Neurostimulator System (RNS) or other neurostimulation for epilepsy device implanted or activated <5 months year prior to enrollment. Stimulation parameters that have been stable for <4 weeks, or Battery life of unit not anticipated to extend for duration of trial. Subject is pregnant, may be pregnant, lactating or planning to be pregnant Any suicidal ideation with intent, with or without a plan within 6 months before Visit 2 (i.e., answering Yes to questions 4 or 5 in the Suicidal Ideation section of the age- specific Columbia-Suicide Severity Rating Scale (C-SSRS) in subjects aged 6 and above who are able to be evaluated Any suicidal behavior within 2 years before Visit 2 (i.e., answering YES to any question in the Suicidal behavior section of the age-specific Columbia-Suicide Severity Rating Scale (C-SSRS) in subjects aged 6 and above who are able to be evaluated. 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 x ULN Subject with total bilirubin [TBL] >2 x ULN (except for Gilbert's syndrome). Active viral hepatitis (B or C) as demonstrated by positive serology at the Screening visit (Visit 1) History of positive antibody/antigen test for human immunodeficiency virus (HIV) If taking Epidiolex, subject may not use other approved cannabidiol or over the counter cannabidiol products Scheduled for epilepsy-related surgery, VNS insertion, or any other stimulators/surgery during the projected course of the study Subject who has taken or used any investigational drug or device in the 4 weeks prior to the screening visit (Visit 1) Concomitant use of medications known to be strong inducers of cytochrome P450 (CYP3A) including, but not limited to: phenobarbital, phenytoin, carbamazepine, primidone, rifampin, troglitazone, St. John's Wort, efavirenz, nevirapine, glucocorticoids (other than topical usage), modafinil, pioglitazone, and rifabutin Evidence of cardiac disease, including unstable angina, myocardial infarction, within the past 2 years, uncontrolled heart failure, major arrhythmias, congenital short QT syndrome Subject with a short QTc interval (<340 msec) or long QTc interval (>460 msec) as confirmed by a repeated electrocardiogram (ECG) Benzodiazepine rescue administered on average more than once a week in the month before Visit 1 Previous exposure to carisbamate or sensitivity/allergy to components of the oral suspension.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 55 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
Interventional Model Description: This double-blind, randomized, placebo-controlled study will evaluate the efficacy of carisbamate 200 mg BID or the pediatric equivalent dose and 300 mg BID or the pediatric equivalent dose for the treatment of seizures associated with Lennox Gastaut syndrome in subjects 4 to 55 years of age.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carisbamate 200 mg BID arm<br>Age: 4 to <12y* Titration: 2 mg/kg BID Maintenance: 4 mg/kg BID Age: ≥12 y Titration: 100 mg BID Maintenance: 200 mg BID | Drug: Carisbamate<br>* Adolescent subjects 12 to 18 years old will receive the same dose as adults. Subjects 4 to < 12 years old in the carisbamate 200 mg BID arm will receive 4 mg/kg (not to exceed a total of 400 mg per day). Subjects 4 to < 12 years old in the carisbamate 300 mg BID arm will receive 5.5 mg/kg (not to exceed a total of 600 mg per day).<br>|
| Experimental: Carisbamate 300 mg BID arm<br>Age: 4 to <12y* Titration: 2.75 mg/kg BID Maintenance: 5.5 mg/kg BID Age: ≥12 y Titration: 150 mg BID Maintenance: 300 mg BID | Drug: Carisbamate<br>* Adolescent subjects 12 to 18 years old will receive the same dose as adults. Subjects 4 to < 12 years old in the carisbamate 200 mg BID arm will receive 4 mg/kg (not to exceed a total of 400 mg per day). Subjects 4 to < 12 years old in the carisbamate 300 mg BID arm will receive 5.5 mg/kg (not to exceed a total of 600 mg per day).<br>|
| Placebo Comparator: Placebo matched to 200 mg BID arm<br>Age: 4 to <12y* Titration: Volume equivalent to 2 mg/kg BID Maintenance: Volume equivalent to 4 mg/kg BID Age: ≥12 y Titration: Volume equivalent to 100 mg BID Maintenance: Volume equivalent to 200 mg BID | Drug: Carisbamate<br>* Adolescent subjects 12 to 18 years old will receive the same dose as adults. Subjects 4 to < 12 years old in the carisbamate 200 mg BID arm will receive 4 mg/kg (not to exceed a total of 400 mg per day). Subjects 4 to < 12 years old in the carisbamate 300 mg BID arm will receive 5.5 mg/kg (not to exceed a total of 600 mg per day).<br>|
| Placebo Comparator: Placebo matched to 300 mg BID arm<br>Age: 4 to <12y* Titration: Volume equivalent to 2.75 mg/kg BID Maintenance: Volume equivalent to 5.5 mg/kg BID Age: ≥12 y Titration: Volume equivalent to 150 mg BID Maintenance: Volume equivalent to 300 mg BID | Drug: Carisbamate<br>* Adolescent subjects 12 to 18 years old will receive the same dose as adults. Subjects 4 to < 12 years old in the carisbamate 200 mg BID arm will receive 4 mg/kg (not to exceed a total of 400 mg per day). Subjects 4 to < 12 years old in the carisbamate 300 mg BID arm will receive 5.5 mg/kg (not to exceed a total of 600 mg per day).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary outcome will be the percentage change from baseline in the total frequency (average per 28 days) of drop seizures with potential to fall (tonic, atonic, tonic-clonic) seizures during the double-blind treatment period. | Efficacy of Carisbamate YKP509 | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of subjects with at least a 50% reduction from baseline in the total frequency of drop seizures (tonic, atonic, tonic-clonic) during the double-blind treatment period. | Efficacy of Carisbamate YKP509 | 3 years | 
| Percentage change from baseline in the frequency of all types of seizures (total seizures) during the double-blind treatment period. | Efficacy of Carisbamate YKP509 | 3 years | 
| Subject/Caregiver Global Impression of Change (S/CGIC) in overall condition score at the last visit. | Efficacy of Carisbamate YKP509- Scoring will be from 1 to 7 with 1 (very much improved) to 7 (very much worse) | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Seizures, Lennox Gastaut Syndrome, Pediatrics, Adults