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

Primary Generalized Epilepsy Clinical Trial

Official title:

A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Cenobamate Adjunctive Therapy in Subjects With PGTC Seizures

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03678753
• Other study ID #: YKP3089C025
• Status: Recruiting
• Phase: Phase 3
• Start date: September 21, 2018
• Est. completion date: July 19, 2024

Study information

• Verified date: April 2024
• Source: SK Life Science, Inc.
• Contact: Sunita Misra, MD
• Phone: 1-402-835-5977
• Email: smisra[@]sklsi.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 170
• Est. completion date: July 19, 2024
• Est. primary completion date: June 19, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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.

Any potential exception to the inclusion as well as exclusion criteria allowing de minimis (clinically trivial and meaningless) variations must be approved by the Medical Monitor.

Related Conditions & MeSH terms

• Epilepsy
• Epilepsy, Generalized
• Primary Generalized Epilepsy
• Seizures

Intervention

Drug:
• 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.
• Placebo
Matching Placebo

Locations

Country	Name	City	State
Australia	Austin Health	Heidelberg
Australia	Children's Health Queensland Hospital	South Brisbane
Bulgaria	Multiprofile Hospital for Active Treatment Puls AD	Blagoevgrad
Bulgaria	MHAT Sv. Ivan Rilski Gorna Oryahovitsa EOOD	Gorna Oryahovitsa	Veliko Tarnovo
Bulgaria	UMHAT Kanev AD	Ruse
Bulgaria	Acibadem City Clinic MHAT Tokuda EAD	Sofia
Bulgaria	Diagnostic Consultative Center Neoclinic EAD	Sofia
Bulgaria	MHAT Lyulin EAD	Sofia
Bulgaria	Diagnostic Consultative Center Equita EOOD	Varna
Bulgaria	Medical Center Medica Plus OOD	Veliko Tarnovo
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	Fakultní nemocnice v Motole	Praha 5	Praha
Czechia	Forbeli s.r.o., Neurologicka ordinace	Praha 6
Czechia	Vestra Clinics, s.r.o.	Rychnov Nad Knežnou
Czechia	Neurologicka ambulance MUDr.Monika Zahumenska	Zlín
Germany	Charite - Universitätsmedizin Berlin - Sozialpädiatrisches Zentrum	Berlin
Germany	Universitätsklinikum Jena	Jena
Germany	Universitätsklinikum Schleswig-Holstein - Campus Kiel	Kiel
Germany	Sächsisches Epilepsiezentrum Kleinwachau gGmbH	Radeberg
Hungary	Semmelweis Egyetem	Budapest
Hungary	Debreceni Egyetem Klinikai Központ, Gyermekgyógyászati Intézet Nagyerdei krt. 98	Debrecen
Hungary	Csongrád Megyei Egészségügyi Elláto Központ Ideggyógyászati Osztály	Hodmezovasarhely
Korea, Republic of	Chungbuk National University Hospital	Cheongju-si	Chungcheongbuk-Do
Korea, Republic of	Keimyung University Dongsan Hospital	Daegu
Korea, Republic of	CHA Bundang Medical Center	Seongnam-si	Gyeonggi-do
Korea, Republic of	SMG-SNU Boramae Medical Center	Seoul	Gyeonggi-Do
Korea, Republic of	Ajou University Hospital	Suwon
Poland	Centrum Medyczne Pratia Katowice	Katowice	Slaskie
Poland	Gornoslaskie Centrum Medyczne - Samodzielny Publiczny Szpital Kliniczny Number 7	Katowice	Silesia
Poland	Gyncentrum Clinic Sp. z.o.o	Katowice	Slaskie
Poland	M.A. LEK A.M. Maciejowscy S.C Centrum Terapii SM	Katowice	Slaskie
Poland	Niepubliczny Zaklad Opieki Zdrowotnej Novo-Med	Katowice	Slaskie
Poland	Niepubliczny Zaklad Opieki Zdrowotnej - Centrum Neurologii Dzieciecej i Leczenia Padaczki	Kielce	Swietokrzyskie
Poland	Centrum Medyczne Plejady	Krakow	Malopolskie
Poland	Wojewódzki Specjalistyczny Szpital Dzieciecy im. sw. Ludwika sw Krakowie	Krakow	Malopolskie
Poland	Centrum Leczenia Padaczki i Migreny	Kraków	Malopolskie
Poland	Centrum Opieki Zdrowotnej Orkan-Med Stec-Michalska S.J.	Ksawerow	Iodzkie
Poland	Instytut Medycyny Wsi im. Witolda Chodzki w Lublinie	Lublin	Lubelskie
Poland	Wojewodzki Szpital Specjalistyczny w Olsztynie	Olsztyn	Warminsko-Mazurskie
Poland	Clinical Research Center Spolka z Ograniczona Odpowiedzialnoscia Medic-R sp. k	Poznan	Wielkopolskie
Poland	NZOZ Poradnia Zdrowia Psychicznego Antonijczuk Boleslaw	Tyniec Maly	Dolnoslaskie
Poland	Centrum Medyczne Warszawa Pratia s.a	Warszawa	Mazowieckie
Poland	Centrum Medyczne Oporów	Wroclaw	Dolnoslaskie
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	Konzílium, s.r.o	Dubnica Nad Váhom	Trencin
Slovakia	NEURES, s.r.o.-Neurologická Ambulancia	Krompachy
Spain	Hospital Clínico San Carlos	Madrid
Spain	Hospital Regional Universitario de Malaga	Malaga
Spain	Hospital Universitario La Fe	Valencia
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	Dnepropetrovsk	Dnipro
Ukraine	Municipal Non-profit Enterprise City Clinical Hospital No.16 of Dnipro City Council, Department of Neurology	Dnipro	Dnipropetrovsk
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	Kyiv City Psychoneurological Hospital ?2	Kiev	Kyiv
Ukraine	Communal Non-Profit Enterprise of Lviv Regional Council Lviv Regional Clinical Hospital, Neurological Department, Antiepileptic Center	Lviv
Ukraine	Municipal Non-Profit Enterprise Odesa Regional Clinical Hospital of Odesa Regional Council, Department of Cerebro-Vascular Diseases with Neurosurgery	Odesa	Odessa
Ukraine	Communal Non-Profit Enterprise Odesa Regional Medical Centre of Mental Health Odesa Regional Council, Department #2	Odessa
Ukraine	Odessa Regional Psychiatric Hospital No. 2,	Odessa
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 Regional Clinical Center of Neurosurgery and Neurology of Zakarpattia Regional Council, Department of Neurosurgery #2	Uzhgorod	Zakarpattia
Ukraine	Municipal Non-profit Enterprise Vinnytsia Regional Clinical Psychoneurological Hospital named after Acad. O.I. Yushchenko of Vinnytsia Regional Council, Department of Neurology #3	Vinnytsya
Ukraine	Municipal Non-Profit Enterprise Zaporizhzhia Regional Clinical Hospital Of Zaporizhzhia Regional Council	Zaporozhye	Zaporizhzhya
United States	PMG Research of McFarland Clinic	Ames	Iowa
United States	Children's Healthcare of Atlanta	Atlanta	Georgia
United States	Clinical Integrative Research Center of Atlanta, CIRCA	Atlanta	Georgia
United States	Child Neurology Consultants of Austin	Austin	Texas
United States	Mid-Atlantic Epilepsy and Sleep Center	Bethesda	Maryland
United States	Consultants in Epilepsy and Neurology	Boise	Idaho
United States	New York Presbyterian Hospital	Brooklyn	New York
United States	UBMD Neurology	Buffalo	New York
United States	Rush University	Chicago	Illinois
United States	Colorado Springs Neurological Associates	Colorado Springs	Colorado
United States	University of Missouri Health Care	Columbia	Missouri
United States	Ohio Health Research and Innovation Institute	Columbus	Ohio
United States	Duke University Children's Health Center	Durham	North Carolina
United States	Michigan State University	East Lansing	Michigan
United States	JFK Medical Center- The Neuroscience Institute	Edison	New Jersey
United States	ANRC Research	El Paso	Texas
United States	Neuro Pain Medical Center	Fresno	California
United States	Minneapolis Clinic of Neurology Golden Valley	Golden Valley	Minnesota
United States	Children's Hospital of Colorado	Grand Junction	Colorado
United States	Northeast Regional Epilepsy Group	Hackensack	New Jersey
United States	Hawaii Pacific Neuroscience	Honolulu	Hawaii
United States	Baylor College of Medicine	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	University of Kentucky	Lexington	Kentucky
United States	LeBonheur Children's Medical Center	Memphis	Tennessee
United States	Brainstorm Research	Miami	Florida
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Saint Peter's University Hospital	New Brunswick	New Jersey
United States	Florida Hospital Medical Group	Orlando	Florida
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Temple University Lewis Katz School of Medicine	Philadelphia	Pennsylvania
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Valley Medical Center	Renton	Washington
United States	Carilion Clinic	Roanoke	Virginia
United States	University of Utah / Primary Children's Hospital	Salt Lake City	Utah
United States	Maine Medical Center	Scarborough	Maine
United States	MultiCare Institute for Research and Innovation	Spokane	Washington
United States	University of South Florida	Tampa	Florida
United States	University of Toledo	Toledo	Ohio
United States	Center for Neurosciences	Tucson	Arizona
United States	Five Towns Neuroscience Research	Woodmere	New York

Sponsors (1)

Lead Sponsor	Collaborator
SK Life Science, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Bulgaria,  Czechia,  Germany,  Hungary,  Korea, Republic of,  Poland,  Slovakia,  Spain,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Seizure Diary	Daily seizure diary that contains type and frequency of seizures	28 Days