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

Seizures Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05219617
• Other study ID #: YKP509C003
• Status: Recruiting
• Phase: Phase 3
• Start date: April 28, 2022
• Est. completion date: June 2026

Study information

• Verified date: May 2024
• Source: SK Life Science, Inc.
• Contact: Barbara Remes
• Phone: 201-421-3810
• Email: bremes[@]sklsi.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 252
• Est. completion date: June 2026
• Est. primary completion date: June 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 4 Years to 55 Years

Eligibility

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.

Related Conditions & MeSH terms

• Lennox Gastaut Syndrome
• Seizures
• Syndrome

Intervention

Drug:
• Carisbamate
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 BID (not to exceed 200 mg BID [or 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 BID (not to exceed 300 mg BID [or a total of 600 mg per day]).

Locations

Country	Name	City	State
Argentina	Hospital de Ninos de La Santisma Trinidad	Córdoba	Cordoba
Argentina	Resolution Psychopharmacology Research Institute	Mendoza
Australia	Austin Hosptial	Heidelberg
Australia	Alfred Health	Melbourne
Australia	Perth's Children Hospital	Nedlands
Australia	Queensland Children's Hospital	South Brisbane
Colombia	Fundacion Hospital Universidad del Norte	Barranquilla
Colombia	Fundacion Valle del Lili/Clinic - Outpatient	Cali
Colombia	CliniSalud del Sur S.A.S - Centro de Investigación	Envigado
Colombia	Hospital Pabloe Tubon Uribe	Medellín
Colombia	Institutio Neurologico de Colombia	Medellín
Germany	Universitatsklinikum Erangen	Erlangen	Bayern
Germany	Kleinwachau Sächsisches Epilepsiezentrum	Radeberg	Sachsen
Greece	Iaso Children's Hospital	Maroúsi	Attiki
Israel	Soroka University Medical Centre	Be'er Sheva
Israel	Hadassah Medical Center	Jerusalem
Israel	Sheba Medical Center	Ramat Gan
Israel	Tela Viv Sourlasky Medical Center	Tel Aviv Yafo	Tel Aviv
Italy	Azienda Ospedaliero Universitaria A Meyer - INCIPIT - PIN	Calambrone
Italy	Istituto G Gaslini Ospedale Pediatrico IRCCS - INCIPIT - PIN	Genova	Liguria
Italy	ASST Fatebenefratelli Sacco - Ospedale dei Bambini Vittore Buzzi	Milano	Lombardia
Italy	ASST Santi Paolo E Carlo - Azienda Universitaria-Polo Universitaria - San Paolo	Milano
Italy	Fondazione IRCCS Di Rilievo Nazionale Instituto	Milano	Lombardia
Italy	Azienda Ospedaliera Universitaria Integrata Di Verona	Verona
Korea, Republic of	Kyungpook National University Chilgok Hospital	Daegu
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Mexico	Neurociencias Estudios Clinicos S.C.	Culiacán
Mexico	Hospital Civil Fray Antonio Alcalde	Guadalajara	Jalisco
Mexico	Clinstile, S.A. de C.V.	Mexico City
Poland	Centrum Medyczne Plejady	Kraków
Poland	Szpital Kliniczny im.H.Swiecickiego Uniwersytetu Medycznego im.K.Marcinkowskiego w Poznaniu-Dluga1/2	Poznan	Wielkopolskie
Portugal	Hospital Garcia de Orta	Almada	Setubal
Portugal	Centro Hospitalar de Lisboa Norte, EPE	Lisboa
Portugal	Centro Hospitalar de Lisboa Ocidental, EPE - Hospital Sao Francisco Xavier	Lisboa
Portugal	Centro Hospitalar de Sao Joao, EPE	Porto
Serbia	Childrens University Hospital	Belgrade
Serbia	University Clinical Center of Serbia - PPDS	Belgrade
Serbia	University Clinical Center Kragujevac	Kragujevac
Serbia	University Clinical Center Nis	Niš
Serbia	Children and Youth Health Care Institute of Vojvodina	Novi Sad
Spain	Hospital Sant Joan de Deu - PIN	Esplugues De Llobregat	Barcelona
Spain	Hospital Infantil Universitario Niño Jesus - PIN	Madrid
Spain	Hospital Ruber Internacional (Grupo Quironsalud)	Madrid
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	Chang Gung Memorial Hospital	Taoyuan
United States	Austin Epilepsy Care Center - Clinic/Outpatient Facility	Austin	Texas
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	Mid-Atlantic Epilepsy and Sleep Center	Bethesda	Maryland
United States	Consultants in Epilepsy and Neurology PLLC	Boise	Idaho
United States	Montefiore	Bronx	New York
United States	University of Missouri School of Medicine	Columbia	Missouri
United States	Neurology Consultants of Dallas, PA - Hospital	Dallas	Texas
United States	Duke University Clinical Research at Pickett Road	Durham	North Carolina
United States	Northeast Regional Epilepsy Group	Hackensack	New Jersey
United States	University of Florida Health Science Center	Jacksonville	Florida
United States	Bluegrass Epilepsy Research, LLC	Lexington	Kentucky
United States	St. Peters Hospital	New Brunswick	New Jersey
United States	University Medical Center New Orleans	New Orleans	Louisiana
United States	AdventHealth	Orlando	Florida
United States	Stanford University Hospital	Palo Alto	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	Pediatric Epilepsy and Neurology Specialists	Tampa	Florida
United States	University of South Florida	Tampa	Florida
United States	Axcess Medical Research	Wellington	Florida
United States	Virginia Epilepsy and Neurodevelopmental Clinic at WNC	Winchester	Virginia
United States	Wake Forest University - School of Medicine	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
SK Life Science, Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Colombia,  Germany,  Greece,  Israel,  Italy,  Korea, Republic of,  Mexico,  Poland,  Portugal,  Serbia,  Spain,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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.	Efficacy of Carisbamate YKP509	3 years
Other	Percentage change from baseline in non-drop seizures (myoclonic seizures, atypical absence) frequency per 28 days during the during the double-blind treatment period.	Efficacy of Carisbamate YKP509	3 years
Other	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.	Efficacy of Carisbamate YKP509	3 years
Other	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.	Efficacy of Carisbamate YKP509	3 years
Other	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.	Efficacy of Carisbamate YKP509	3 years
Primary	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.	Efficacy of Carisbamate YKP509	3 years
Secondary	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
Secondary	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
Secondary	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