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

Prior treatment

• 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
• 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 prior to Visit 1
• Any clinically significant illness (including COVID-19) in the 4 weeks prior to Visit 1, as evaluated by the Investigator
• 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.
• 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
• 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
• 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.

Other illness

• 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
• 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
• 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)
• Scheduled for epilepsy-related surgery, VNS insertion, or any other stimulators/surgery during the projected course of the study

Lab values

• Subject has clinically significant abnormal laboratory values, in the investigator's opinion, at Visit 1 or time of randomization (Visit 2)
• 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).
• 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)

Age

• 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.

Other

• Current use of felbamate with less than 18 months of continuous exposure
• Subject is pregnant, may be pregnant, lactating or planning to be pregnant
• If taking Epidiolex, subject may not use other approved cannabidiol or over the counter cannabidiol products

• 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) during the 4-week Baseline period preceding randomization (minimum of 4 drop seizures in the first two weeks and 4 in the last two weeks). 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. All drop seizure types must be countable (either as isolated seizures or as countable isolated seizures in a cluster).
• 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 caregiver(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