Clinical trial NCT05219617: Investigate Efficacy and Safety of Carisbamate as Adjunctive Treatment for Seizures Associated With LGS in Children and Adults
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Seizures
Lennox Gastaut Syndrome
Keywords: Seizures
Lennox Gastaut Syndrome
Pediatrics
Adults
Lead sponsor: SK Life Science, Inc.
Sponsor class: INDUSTRY
First posted: 2022-02-02
Enrollment: 252
Sex: ALL
Minimum age (years): 4
Maximum age (years): 55
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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)
* Evaluate the safety, tolerability of carisbamate in the LGS population
* Evaluate steady-state pharmacokinetics of carisbamate in subjects with Lennox Gastaut.

Eligibility criteria: Inclusion Criteria:

1. Subject must have a documented history of Lennox-Gastaut syndrome by:

   1. Evidence of more than one type of seizure, of which at least one should be an atonic or tonic seizure
   2. History of an electroencephalogram (EEG) reporting diagnostic criteria for LGS (abnormal background activity accompanied by slow, spike and wave pattern \<3.0 Hz)
   3. History of developmental delay
2. Male or female subjects
3. Subjects must be age 4-55 years at the time of consent/assent
4. Must have been \<11 years old at the onset of LGS
5. 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).
6. 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
7. 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.
8. 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.
9. Parents or caregivers must be able to keep accurate seizure diaries
10. 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.
11. Subject and/or caregiver(s)/legal representative must be willing and able to give informed assent/consent for participation in the study
12. Subject and their caregiver must be willing and able (in the investigator's opinion) to comply with all study requirements
13. History of COVID-19 vaccination is permitted

Exclusion Criteria:

1. 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
2. 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
3. Subjects who were on adrenocorticotropic hormone (ACTH) therapy in the 6 months prior to baseline
4. Subject on dietary therapy for less than 4 weeks prior to screening visit (Visit 1) or suffers from frequent stooling
5. Current use of felbamate with less than 18 months of continuous exposure
6. 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.
7. Subject who had a history of hypoxia which needed emergency resuscitation within 12 months prior to baseline
8. Status epilepticus within 12 weeks prior to Visit 1
9. Any clinically significant illness (including COVID-19) in the 4 weeks prior to Visit 1, as evaluated by the Investigator
10. Subject has clinically significant abnormal laboratory values, in the investigator's opinion, at Visit 1 or time of randomization (Visit 2)
11. 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
12. 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.
13. Subject is pregnant, may be pregnant, lactating or planning to be pregnant
14. 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
15. 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.
16. 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
17. Subject with total bilirubin \[TBL\] \>2 x ULN (except for Gilbert's syndrome).
18. Active viral hepatitis (B or C) as demonstrated by positive serology at the Screening visit (Visit 1)
19. History of positive antibody/antigen test for human immunodeficiency virus (HIV)
20. If taking Epidiolex, subject may not use other approved cannabidiol or over the counter cannabidiol products
21. Scheduled for epilepsy-related surgery, VNS insertion, or any other stimulators/surgery during the projected course of the study
22. Subject who has taken or used any investigational drug or device in the 4 weeks prior to the screening visit (Visit 1)
23. 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
24. Evidence of cardiac disease, including unstable angina, myocardial infarction, within the past 2 years, uncontrolled heart failure, major arrhythmias, congenital short QT syndrome
25. Subject with a short QTc interval (\<340 msec) or long QTc interval (\>460 msec) as confirmed by a repeated electrocardiogram (ECG)
26. Benzodiazepine rescue administered on average more than once a week in the month before Visit 1
27. Previous exposure to carisbamate or sensitivity/allergy to components of the oral suspension.

Primary outcomes:
measure: Primary outcome will be the percentage change from baseline in the total frequency (average per 28 days) of countable drop seizures with potential to fall (tonic, atonic, tonic-clonic) seizures during the double-blind treatment period.
timeFrame: 3 years
Secondary outcomes:
measure: 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.
timeFrame: 3 years
measure: Percentage change from baseline in the frequency of all types of seizures (total seizures) during the double-blind treatment period.
timeFrame: 3 years
measure: Subject/Caregiver Global Impression of Change (S/CGIC) in overall condition score at the last visit.
timeFrame: 3 years
Other outcomes:
measure: Percentage change from baseline in the 28-day frequency of: drop seizures (tonic, atonic, tonic-clonic); non-drop seizures (myoclonic seizures, atypical absence); total seizures during the maintenance phase of the double-blind treatment period.
timeFrame: 3 years
measure: Percentage change from baseline in non-drop seizures (myoclonic seizures, atypical absence) frequency per 28 days during the during the double-blind treatment period.
timeFrame: 3 years
measure: 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 maintenance phase of the double-blind treatment period.
timeFrame: 3 years
measure: Proportion of subjects with a 75%, 90% and 100% response rate for drop seizures (tonic, atonic, tonic-clonic), non-drop seizures, and total seizures during the double-blind treatment period.
timeFrame: 3 years
measure: Proportion of subjects with a 75%, 90% and 100% response rate for drop seizures (tonic, atonic, tonic-clonic), non-drop seizures, and total seizures during the maintenance phase of the double-blind treatment period.
timeFrame: 3 years
Locations:
city: Palo Alto
country: United States
facility: Stanford University Hospital
state: California
city: Jacksonville
country: United States
facility: University of Florida Health Science Center
state: Florida
city: Orlando
country: United States
facility: AdventHealth
state: Florida
city: Tampa
country: United States
facility: Pediatric Epilepsy and Neurology Specialists
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Wellington
country: United States
facility: Axcess Medical Research
state: Florida
city: Boise
country: United States
facility: Consultants in Epilepsy and Neurology PLLC
state: Idaho
city: Lexington
country: United States
facility: Bluegrass Epilepsy Research, LLC
state: Kentucky
city: New Orleans
country: United States
facility: University Medical Center New Orleans
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Bethesda
country: United States
facility: Mid-Atlantic Epilepsy and Sleep Center
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Columbia
country: United States
facility: University of Missouri School of Medicine
state: Missouri
city: Hackensack
country: United States
facility: Northeast Regional Epilepsy Group
state: New Jersey
city: New Brunswick
country: United States
facility: St. Peters Hospital
state: New Jersey
city: Bronx
country: United States
facility: Montefiore
state: New York
city: Durham
country: United States
facility: Duke University Clinical Research at Pickett Road
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University - School of Medicine
state: North Carolina
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Austin
country: United States
facility: Austin Epilepsy Care Center - Clinic/Outpatient Facility
state: Texas
city: Dallas
country: United States
facility: Neurology Consultants of Dallas, PA - Hospital
state: Texas
city: Winchester
country: United States
facility: Virginia Epilepsy and Neurodevelopmental Clinic at WNC
state: Virginia
city: Córdoba
country: Argentina
facility: Hospital de Ninos de La Santisma Trinidad
state: Cordoba
city: Mendoza
country: Argentina
facility: Resolution Psychopharmacology Research Institute
city: Heidelberg
country: Australia
facility: Austin Hosptial
city: Melbourne
country: Australia
facility: Alfred Health
city: Nedlands
country: Australia
facility: Perth's Children Hospital
city: South Brisbane
country: Australia
facility: Queensland Children's Hospital
city: Barranquilla
country: Colombia
facility: Fundacion Hospital Universidad del Norte
city: Cali
country: Colombia
facility: Fundacion Valle del Lili/Clinic - Outpatient
city: Envigado
country: Colombia
facility: CliniSalud del Sur S.A.S - Centro de Investigación
city: Medellín
country: Colombia
facility: Hospital Pabloe Tubon Uribe
city: Medellín
country: Colombia
facility: Institutio Neurologico de Colombia
city: Erlangen
country: Germany
facility: Universitatsklinikum Erangen
state: Bayern
city: Radeberg
country: Germany
facility: Kleinwachau Sächsisches Epilepsiezentrum
state: Sachsen
city: Maroúsi
country: Greece
facility: Iaso Children's Hospital
state: Attiki
city: Budapest
country: Hungary
facility: Orszagos Mentalis, Ideggyogyaszati es Idegsebezeti Intezet
city: Budapest
country: Hungary
facility: Semmelweis Egyetem Idegsebeszeti es Neurointervencios Klinika
city: Tel Aviv Yafo
country: Israel
facility: Tela Viv Sourlasky Medical Center
state: Tel Aviv
city: Be'er Sheva
country: Israel
facility: Soroka University Medical Centre
city: Jerusalem
country: Israel
facility: Hadassah Medical Center
city: Ramat Gan
country: Israel
facility: Sheba Medical Center
city: Genova
country: Italy
facility: Istituto G Gaslini Ospedale Pediatrico IRCCS - INCIPIT - PIN
state: Liguria
city: Milano
country: Italy
facility: ASST Fatebenefratelli Sacco - Ospedale dei Bambini Vittore Buzzi
state: Lombardia
city: Milano
country: Italy
facility: Fondazione IRCCS Di Rilievo Nazionale Instituto
state: Lombardia
city: Firenze
country: Italy
facility: Azienda Ospedaliero Universitaria A Meyer - INCIPIT - PIN
city: Milano
country: Italy
facility: ASST Santi Paolo E Carlo - Azienda Universitaria-Polo Universitaria - San Paolo
city: Verona
country: Italy
facility: Azienda Ospedaliera Universitaria Integrata Di Verona
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Chilgok Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Guadalajara
country: Mexico
facility: Hospital Civil Fray Antonio Alcalde
state: Jalisco
city: Culiacán
country: Mexico
facility: Neurociencias Estudios Clinicos S.C.
city: Mexico City
country: Mexico
facility: Clinstile, S.A. de C.V.
city: Poznan
country: Poland
facility: Szpital Kliniczny im.H.Swiecickiego Uniwersytetu Medycznego im.K.Marcinkowskiego w Poznaniu-Dluga1/2
state: Wielkopolskie
city: Kraków
country: Poland
facility: Centrum Medyczne Plejady
city: Almada
country: Portugal
facility: Hospital Garcia de Orta
state: Setubal
city: Lisboa
country: Portugal
facility: Centro Hospitalar de Lisboa Norte, EPE
city: Lisboa
country: Portugal
facility: Centro Hospitalar de Lisboa Ocidental, EPE - Hospital Sao Francisco Xavier
city: Porto
country: Portugal
facility: Centro Hospitalar de Sao Joao, EPE
city: Belgrade
country: Serbia
facility: Childrens University Hospital
city: Belgrade
country: Serbia
facility: University Clinical Center of Serbia - PPDS
city: Kragujevac
country: Serbia
facility: University Clinical Center Kragujevac
city: Niš
country: Serbia
facility: University Clinical Center Nis
city: Novi Sad
country: Serbia
facility: Children and Youth Health Care Institute of Vojvodina
city: Esplugues De Llobregat
country: Spain
facility: Hospital Sant Joan de Deu - PIN
state: Barcelona
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Niño Jesus - PIN
city: Madrid
country: Spain
facility: Hospital Ruber Internacional (Grupo Quironsalud)
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taoyuan
country: Taiwan
facility: Chang Gung Memorial Hospital
Study officials:
affiliation: SK Life Science, Inc.
name: Marc Kamin, MD
role: STUDY_DIRECTOR
References: