Randomized, Double-Blind Study to Evaluate Efficacy and Safety of Cenobamate Adjunctive Therapy in PGTC Seizures

NCT ID: NCT03678753

Last Updated: 2025-07-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 169 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-09-21
• Study Completion Date: 2025-05-26

Brief Summary

This trial is intended to study the safety and effectiveness of an new anti-epileptic drug (AED) on Primary Generalized Tonic-Clonic (PGTC) Seizures. Eligible Subjects, adults and adolescents, will continue to take their usual AEDs and receive either cenobamate or placebo. Subjects will have a 50% chance or receiving cenobamate or placebo (sugar pill). Subjects will initially receive 12.5 mg of cenobamate or placebo (study drug) and increase the dose every two weeks until they reach a target dose of 200 mg. Subjects will take study drug at approximately the same time in the morning (once a day) with or without food. If tolerability issues arise, dosing can be changed to evening. Also, once a subject reaches 200 mg, the dose can be decreased one time to 150 mg, if necessary. The treatment period is 22 weeks and there is a 3 week follow up period, which includes a one week decrease in study drug to 100 mg prior to stopping. Adolescents will follow the same every two week regimen and receive cenobamate as an oral suspension based on weight. Subjects who complete may be eligible for an extension study and will not have to complete the follow up period. Subjects will track their seizure types and frequency in a diary throughout the study.

Detailed Description

This randomized, double-blind, placebo controlled trial is designed to evaluate safety, efficacy, and pharmacokinetics of cenobamate adjunctive therapy as compared to placebo on PGTC seizures in subject with idiopathic generalized epilepsy. Subjects will be randomized to receive either cenobamate or placebo on a 1:1 basis. The study will have three periods, pre-randomization period where a baseline seizure frequency is established, treatment period and follow up period. The treatment period consists of a 10 week titration phase where subjects are titrated slowly until they reach the target dose and a maintenance phase. During the titration phase, subjects will receive 12.5 mg study drug, followed by 25 mg, 50 mg, 100 mg, and 150 mg study drug every two weeks. During the maintenance phase, subjects will receive the target dose of 200 mg study drug or adolescent equivalent. Subjects will take their once daily dose of study drug at approximately the same in the morning with or without food. If tolerability issues arise, subjects can switch to evening dosing. There is also an option to down-titrate to 150 mg study drug, one time only. If tolerability issues continue, subjects may be discontinued. Upon completion of the maintenance phase, eligible subjects will have an opportunity to enroll in an open-label safety study. Subjects who discontinue early or do not wish to participate in this additional study will complete the three week follow up period. Subjects may receive a one week down titration to 100 mg and return for a follow up visit 2 weeks later. Adolescents will follow the same every two week regimen and receive cenobamate as an oral suspension based on weight Throughout the study, subjects will keep a diary containing the type and frequency of seizures. This will be the primary efficacy measure.

Conditions

Primary Generalized Epilepsy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Cenobamate

Cenobamate 12.5 mg tablet once a day for two weeks, 25 mg tablet once a day for two weeks, 50 mg tablet once a day for two weeks, 100 mg tablets once a day for two weeks, 150 mg tablets once a day for two weeks and 200 mg tablets once a day for twelve weeks. Adolescents will follow the same every two week regimen and receive cenobamate as an oral suspension based on weight.

Group Type: EXPERIMENTAL

Cenobamate

Intervention Type: DRUG

12.5 mg tablet, 25 mg tablet, 50 mg tablet, 100 mg tablets, 150 mg tablets, 200 mg tablets. Adolescents will follow the same every two week regimen and receive cenobamate as an oral suspension based on weight.

Placebo

Matching placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Matching Placebo

Interventions

Cenobamate

12.5 mg tablet, 25 mg tablet, 50 mg tablet, 100 mg tablets, 150 mg tablets, 200 mg tablets. Adolescents will follow the same every two week regimen and receive cenobamate as an oral suspension based on weight.

Intervention Type: DRUG

Placebo

Matching Placebo

Intervention Type: DRUG

Other Intervention Names

YKP3089; PBO

Eligibility Criteria

Inclusion Criteria

1. Subject is male or female and aged ≥12 years.

2. Written informed consent signed by the subject or legal guardian, or legally authorized representative (LAR), prior to entering the study, in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. Age- appropriate assent will be obtained for adolescents. If the written informed consent is provided by the legal guardian because the subject is unable to do so, a written or verbal assent from the subject must also be obtained. As required by country-specific regulations, only the subject may sign the Informed Consent Form (ICF) in accordance with ICH guidelines.

3. Female subjects of childbearing potential are willing to use an acceptable form of birth control

4. Subject has a clinical diagnosis of PGTC seizures (with or without other subtypes of generalized seizures) in the setting of idiopathic generalized epilepsy.

5. Subject experiences at least 5 PGTC seizures in 12 weeks during the Pre-Randomization Period.

6. Subject has had a routine electroencephalogram (EEG) within 5 years prior to Visit1 (Screening/Baseline) or during the Pre-Randomization Period with electroencephalographic features consistent with idiopathic generalized epilepsy; other concomitant anomalies must be explained by adequate past medical history.

7. Subject has undergone computed tomography (CT) or magnetic resonance imaging (MRI) within 10 years prior to Visit 1 (Screening/Baseline) or during the Pre-Randomization Period that ruled out a progressive cause of epilepsy.

8. Subject is currently receiving 1 to a maximum of 3 concomitant AEDs with fixed dosing regimens for a minimum of 30 days prior to Visit 1 (Screening/Baseline).

1. Benzodiazepines (except diazepam, see Exclusion Criterion No.7) taken at least once per week during the 30 days prior to Visit 1 (Screening/Baseline) for epilepsy, anxiety, or sleep disorder will be counted as 1 AED and the dosage must be continued unchanged throughout the study. Therefore, only a maximum of 2 additional approved AEDs will be allowed. (See Exclusion Criterion No. 10 for intermittent benzodiazepine rescue parameters.)

2. Subjects receiving felbamate as a concomitant AED must meet the following criteria: i. Have a 2-year history of felbamate use and a history of a fixed dosing regimen for a minimum of 60 days prior to Visit 1 (Screening/Baseline). ii. No prior or known history of hepatotoxicity or hematologic disorder due to felbamate.

9. Subject with an implanted vagal nerve or deep brain stimulator will be allowed if the stimulator was implanted at least 5 months prior to Visit 1 (Screening/Baseline) and the stimulator parameters are not changed for 30 days prior to Visit 1 and for the duration of the study.

10. Subject taking a ketogenic diet will be allowed as long as the diet has been stable for at least 3 months prior to Visit 1 (Screening/Baseline) and will remain stable for the duration of the study.

Exclusion Criteria

1. Female subjects who are pregnant (or planning to become pregnant during the study), lactating, or breast-feeding.

2. Subject has a history o f status epilepticus that required hospitalization within 12 months prior to Visit 1 (Screening/Baseline).

3. Subject has PGTC seizure clusters where individual seizures cannot be counted or classified.

4. Subject has a history of non-epileptic psychogenic seizures.

5. Subject has a concomitant diagnosis of Partial Onset Seizures (POS).

6. Subject has a clinical diagnosis of Lennox-Gastaut syndrome.

7. Subject is currently taking (within the 30 days prior to Visit 1 [Screening/Baseline]) any of the following medications: diazepam (for any reason other than as intermittent benzodiazepine rescue medication), phenytoin, mephenytoin, fosphenytoin, phenobarbital, primidone, ethotoin, clopidogrel, fluvoxamine, amitriptyline, clomipramine, bupropion, methadone, ifosfamide, cyclophosphamide, or efavirenz.

8. Subject has participated in previous cenobamate clinical studies.

9. Subject has a history of vigabatrin use within 5months prior to Visit 1 (Screening/Baseline), or the subject plans to begin treatment with vigabatrin during the study.

a) A subject with a history of vigabatrin use that ended more than 5 months prior to Visit1 may be enrolled after documented evidence of no vigabatrin-associated clinically significant abnormality in an automated visual perimetry test.

10. Subject has a history of intermittent use of rescue benzodiazepines (i.e., 1 to 2 doses over a 24-hour period is considered a 1-time rescue) 4 or more times within the 30 days prior to Visit 1 (Screening/Baseline).

11. Subject has received an investigational drug or device within 30 days prior to Visit 1 (Screening/Baseline).

12. Subject has a history of drug or alcohol dependency or abuse within 2 years prior to Visit 1 (Screening/Baseline).

13. Subject tests positive, via urine drug screen at Visit 1 (Screening/Baseline), for illicit drugs not legalized in your region/state, or for a drug that has not been prescribed (e.g., certain opiates).

14. Subject has a history of any serious drug-induced hypersensitivity reaction (including, but not limited to, Stevens Johnson syndrome, toxic epidermal necrolysis, or DRESS) or any drug-related rash requiring hospitalization.

15. History of AED-associated rash that involved conjunctiva or mucosae.

16. History of more than one non-serious drug-related hypersensitivity reaction that required discontinuation of the medication.

17. Subject has evidence of clinically significant abnormalities or disease (e.g., psychiatric, cardiac, respiratory, gastrointestinal, hepatic [aspartate aminotransferase (AST) or alanine aminotransferase (ALT) more than 2 times the upper limit of normal (ULN), or total or direct bilirubin not more than ULN], or renal disease) that, in the opinion of the Principal Investigator, could affect the subject's safety or conduct of the study.

18. Presence of congenital short QT syndrome or relevant replicated change in QT/QTc interval less than 340 msec on ECG.

19. Subject has any significant active Central Nervous System (CNS) infection, demyelinating disease, degenerative neurologic disease or any CNS disease deemed to be progressive during the course of the study that may confound the interpretation of the study results.

20. Subject has a creatinine clearance less than 50 mL/min, as calculated by Cockcroft-Gault equation.

21. Subject has an absolute neutrophil count less than 1500/µL.

22. Subject has platelet count lower than 80,000/µL in subjects treated with valproate.

23. Subject has a history of positive antibody/antigen test for hepatitis A, hepatitis B, hepatitis C, or HIV.

24. Subject has any suicidal ideation (with intent with or without a plan) at Visit 1 (Screening/Baseline) or Visit 4 (Randomization) (i.e., answering YES to Question 4 and/or Question 5 on the Suicidal Ideation section of the C-SSRS).

25. Subject has more than 1 lifetime suicide attempt.

26. Subject is a staff member or immediate family member of study staff.

27. Previous exposure to cenobamate or sensitivity/allergy to components of the oral suspension.

• Minimum Eligible Age: 12 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

SK Life Science, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sunita Misra, MD

Role: STUDY_DIRECTOR

SK Life Science, Inc.

Locations

Phoenix Children's Hospital

Phoenix, Arizona, United States

Center for Neurosciences

Tucson, Arizona, United States

Neuro Pain Medical Center

Fresno, California, United States

Colorado Springs Neurological Associates

Colorado Springs, Colorado, United States

Children's Hospital of Colorado

Grand Junction, Colorado, United States

Brainstorm Research

Miami, Florida, United States

Florida Hospital Medical Group

Orlando, Florida, United States

University of South Florida

Tampa, Florida, United States

Clinical Integrative Research Center of Atlanta, CIRCA

Atlanta, Georgia, United States

Children's Healthcare of Atlanta

Atlanta, Georgia, United States

Hawaii Pacific Neuroscience

Honolulu, Hawaii, United States

Consultants in Epilepsy and Neurology

Boise, Idaho, United States

Rush University

Chicago, Illinois, United States

Indiana University

Indianapolis, Indiana, United States

PMG Research of McFarland Clinic

Ames, Iowa, United States

University of Kentucky

Lexington, Kentucky, United States

Maine Medical Center

Scarborough, Maine, United States

Mid-Atlantic Epilepsy and Sleep Center

Bethesda, Maryland, United States

Michigan State University

East Lansing, Michigan, United States

Minneapolis Clinic of Neurology Golden Valley

Golden Valley, Minnesota, United States

Mayo Clinic - Rochester

Rochester, Minnesota, United States

University of Missouri Health Care

Columbia, Missouri, United States

JFK Medical Center- The Neuroscience Institute

Edison, New Jersey, United States

Northeast Regional Epilepsy Group

Hackensack, New Jersey, United States

Saint Peter's University Hospital

New Brunswick, New Jersey, United States

New York Presbyterian Hospital

Brooklyn, New York, United States

UBMD Neurology

Buffalo, New York, United States

Five Towns Neuroscience Research

Woodmere, New York, United States

Duke University Children's Health Center

Durham, North Carolina, United States

Ohio Health Research and Innovation Institute

Columbus, Ohio, United States

University of Toledo

Toledo, Ohio, United States

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States

Thomas Jefferson University

Philadelphia, Pennsylvania, United States

Temple University Lewis Katz School of Medicine

Philadelphia, Pennsylvania, United States

LeBonheur Children's Medical Center

Memphis, Tennessee, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Child Neurology Consultants of Austin

Austin, Texas, United States

ANRC Research

El Paso, Texas, United States

Baylor College of Medicine

Houston, Texas, United States

University of Utah / Primary Children's Hospital

Salt Lake City, Utah, United States

Carilion Clinic

Roanoke, Virginia, United States

Valley Medical Center

Renton, Washington, United States

MultiCare Institute for Research and Innovation

Spokane, Washington, United States

Austin Health

Heidelberg, , Australia

Children's Health Queensland Hospital

South Brisbane, , Australia

MHAT Sv. Ivan Rilski Gorna Oryahovitsa EOOD

Gorna Oryahovitsa, Veliko Tarnovo, Bulgaria

Multiprofile Hospital for Active Treatment Puls AD

Blagoevgrad, , Bulgaria

UMHAT Kanev AD

Rousse, , Bulgaria

MHAT Lyulin EAD

Sofia, , Bulgaria

Acibadem City Clinic MHAT Tokuda EAD

Sofia, , Bulgaria

Diagnostic Consultative Center Neoclinic EAD

Sofia, , Bulgaria

Diagnostic Consultative Center Equita EOOD

Varna, , Bulgaria

Medical Center Medica Plus OOD

Veliko Tarnovo, , Bulgaria

Fakultní nemocnice v Motole

Prague, Prague, Czechia

Fakultni nemocnice u sv. Anny v Brne, 1. Neurologicka klinika

Brno, , Czechia

Nestatni zdravotnicke zarizeni, privatni ordinance neurologie

Hradec Králové, , Czechia

Cerebrovaskularni poradna, s.r.o.

Ostrava-Poruba, , Czechia

Cerebovaskularni poradna s.r.o.

Ostrava-Vitkovice, , Czechia

Forbeli s.r.o., Neurologicka ordinace

Prague, , Czechia

Vestra Clinics, s.r.o.

Rychnov nad Kněžnou, , Czechia

Neurologicka ambulance MUDr.Monika Zahumenska

Zlín, , Czechia

LEPL Tbilisi State Medical University Givi Zhvania Academic Clinic of Pediatry

Tbilisi, , Georgia

Institute of Neurology and Neuropsychology LTD

Tbilisi, , Georgia

Charite - Universitätsmedizin Berlin - Sozialpädiatrisches Zentrum

Berlin, , Germany

Universitätsklinikum Jena

Jena, , Germany

Universitätsklinikum Schleswig-Holstein - Campus Kiel

Kiel, , Germany

Sächsisches Epilepsiezentrum Kleinwachau gGmbH

Radeberg, , Germany

Semmelweis Egyetem

Budapest, , Hungary

Debreceni Egyetem Klinikai Központ, Gyermekgyógyászati Intézet Nagyerdei krt. 98

Debrecen, , Hungary

Csongrád Megyei Egészségügyi Elláto Központ Ideggyógyászati Osztály

Hódmezővásárhely, , Hungary

Clinical Research Center Spolka z Ograniczona Odpowiedzialnoscia Medic-R sp. k

Poznan, Greater Poland Voivodeship, Poland

Centrum Opieki Zdrowotnej Orkan-Med Stec-Michalska S.J.

Ksawerów, Iodzkie, Poland

Centrum Leczenia Padaczki i Migreny

Krakow, Lesser Poland Voivodeship, Poland

Centrum Medyczne Plejady

Krakow, Lesser Poland Voivodeship, Poland

Wojewódzki Specjalistyczny Szpital Dziecięcy im. sw. Ludwika sw Krakowie

Krakow, Lesser Poland Voivodeship, Poland

NZOZ Poradnia Zdrowia Psychicznego Antonijczuk Boleslaw

Tyniec Mały, Lower Silesian Voivodeship, Poland

Centrum Medyczne Oporów

Wroclaw, Lower Silesian Voivodeship, Poland

Instytut Medycyny Wsi im. Witolda Chodzki w Lublinie

Lublin, Lublin Voivodeship, Poland

Centrum Medyczne Warszawa Pratia s.a

Warsaw, Masovian Voivodeship, Poland

Centrum Medyczne Pratia Katowice

Katowice, Silesian Voivodeship, Poland

M.A. LEK A.M. Maciejowscy S.C Centrum Terapii SM

Katowice, Silesian Voivodeship, Poland

Gornoslaskie Centrum Medyczne - Samodzielny Publiczny Szpital Kliniczny Number 7

Katowice, Silesian Voivodeship, Poland

Niepubliczny Zaklad Opieki Zdrowotnej Novo-Med

Katowice, Silesian Voivodeship, Poland

Gyncentrum Clinic Sp. z.o.o

Katowice, Silesian Voivodeship, Poland

Wojewodzki Szpital Specjalistyczny w Olsztynie

Olsztyn, Warmian-Masurian Voivodeship, Poland

Niepubliczny Zakład Opieki Zdrowotnej - Centrum Neurologii Dziecięcej i Leczenia Padaczki

Kielce, Świętokrzyskie Voivodeship, Poland

Konzílium, s.r.o

Dubnica nad Váhom, Trenčín Region, Slovakia

MUDr. Beata Dupejova, neurologická ambulncia, s.r.o

Banská Bystrica, , Slovakia

IN MEDIC s.r.o

Bardejov, , Slovakia

Narodny Ustav Detskych Chorob

Bratislava, , Slovakia

MEDBAJ, s.r.o., Neurologicka ambulancia, Nemocnicna 1944/10

Dolný Kubín, , Slovakia

NEURES, s.r.o.-Neurologická Ambulancia

Krompachy, , Slovakia

CHA Bundang Medical Center

Seongnam-si, Gyeonggi-do, South Korea

SMG-SNU Boramae Medical Center

Seoul, Gyeonggi-do, South Korea

Chungbuk National University Hospital

Cheongju-si, North Chungcheong, South Korea

Ajou University Hospital

Suwon, , South Korea

Hospital Clínico San Carlos

Madrid, , Spain

Hospital Regional Universitario de Malaga

Málaga, , Spain

Hospital Universitario La Fe

Valencia, , Spain

Municipal Non-profit Enterprise City Clinical Hospital No.16 of Dnipro City Council, Department of Neurology

Dnipro, Dnipropetrovsk Oblast, Ukraine

Communal Enterprise Dnipropetrovsk Regional Clinical Hospital n.a. I.I. Mechnykov of Dnipropetrovsk Regional Council, Regional Center of Psychosomatic Disorders based on Psychoneurology Department

Dnipro, Dnipro, Ukraine

Kyiv City Psychoneurological Hospital №2

Kiev, Kyiv Oblast, Ukraine

Municipal Non-Profit Enterprise Odesa Regional Clinical Hospital of Odesa Regional Council, Department of Cerebro-Vascular Diseases with Neurosurgery

Odesa, Odesa Oblast, Ukraine

Municipal Non-profit Enterprise Regional Clinical Center of Neurosurgery and Neurology of Zakarpattia Regional Council, Department of Neurosurgery #2

Uzhhorod, Zakarpattia Oblast, Ukraine

Municipal Non-Profit Enterprise Zaporizhzhia Regional Clinical Hospital Of Zaporizhzhia Regional Council

Zaporizhzhya, Zaporizhzhya, Ukraine

Communal Enterprise Regional Medical Center of Family Health of the Dnipropetrovsk Regional Council

Dnipro, , Ukraine

Communal Non-commercial Enterprise City Children's Clinical Hospital 6 of Dnipro City Council

Dnipro, , Ukraine

Communal Enterprise Dnipropetrovsk Regional Clinical Hospital n.a. I.I. Mechnykov of Dnipropetrovsk Regional Council

Dnipropetrovsk, , Ukraine

Municipal Non-profit Enterprise Prykarpattia Regional Clinical Center for Mental Health of Ivano-Frankivsk Regional Council

Ivano-Frankivsk, , Ukraine

Communal Non-Commercial Enterprise of Kharkiv Regional Council Regional Clinical Psychiatric Hospital #3

Kharkiv, , Ukraine

Communal Non-Profit Enterprise of Lviv Regional Council Lviv Regional Clinical Hospital, Neurological Department, Antiepileptic Center

Lviv, , Ukraine

Communal Non-Profit Enterprise Odesa Regional Medical Centre of Mental Health Odesa Regional Council, Department #2

Odesa, , Ukraine

Odessa Regional Psychiatric Hospital No. 2,

Odesa, , Ukraine

Communal Enterprise Poltava Regional Clinical Psychiatric Hospital named after O.F. Maltsev of Poltava Regional Council

Poltava, , Ukraine

Municipal Non-Profit Enterprise Ternopil Regional Clinical Psychoneurological Hospital of Ternopil Regional Council, Department of Neurology #2

Ternopil, , Ukraine

Municipal Non-profit Enterprise Vinnytsia Regional Clinical Psychoneurological Hospital named after Acad. O.I. Yushchenko of Vinnytsia Regional Council, Department of Neurology #3

Vinnytsia, , Ukraine

Countries

United States; Australia; Bulgaria; Czechia; Georgia; Germany; Hungary; Poland; Slovakia; South Korea; Spain; Ukraine

References

Brigo F, Lattanzi S. Cenobamate add-on therapy for drug-resistant focal epilepsy. Cochrane Database Syst Rev. 2024 Aug 1;8(8):CD014941. doi: 10.1002/14651858.CD014941.pub2.

Reference Type: DERIVED

PMID: 39087564 (View on PubMed)

Rosenfeld WE, Ferrari L, Kamin M. Efficacy of cenobamate by focal seizure subtypes: Post-hoc analysis of a phase 3, multicenter, open-label study. Epilepsy Res. 2022 Jul;183:106940. doi: 10.1016/j.eplepsyres.2022.106940. Epub 2022 May 5.

Reference Type: DERIVED

PMID: 35605481 (View on PubMed)

Other Identifiers

YKP3089C025

Identifier Type: -

Identifier Source: org_study_id