Clinical trial NCT03678753: Randomized, Double-Blind Study to Evaluate Efficacy and Safety of Cenobamate Adjunctive Therapy in PGTC Seizures
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Primary Generalized Epilepsy
Keywords: Primary Generalized Tonic-Clonic Seizures
PGTC
Idiopathic Generalized Epilepsy
Generalized Tonic-Clonic Seizures
Lead sponsor: SK Life Science, Inc.
Sponsor class: INDUSTRY
First posted: 2018-09-20
Enrollment: 169
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

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.

Primary outcomes:
measure: Seizure Diary
timeFrame: 28 Days
Secondary outcomes:
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Tucson
country: United States
facility: Center for Neurosciences
state: Arizona
city: Fresno
country: United States
facility: Neuro Pain Medical Center
state: California
city: Colorado Springs
country: United States
facility: Colorado Springs Neurological Associates
state: Colorado
city: Grand Junction
country: United States
facility: Children's Hospital of Colorado
state: Colorado
city: Miami
country: United States
facility: Brainstorm Research
state: Florida
city: Orlando
country: United States
facility: Florida Hospital Medical Group
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Atlanta
country: United States
facility: Clinical Integrative Research Center of Atlanta, CIRCA
state: Georgia
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Honolulu
country: United States
facility: Hawaii Pacific Neuroscience
state: Hawaii
city: Boise
country: United States
facility: Consultants in Epilepsy and Neurology
state: Idaho
city: Chicago
country: United States
facility: Rush University
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Ames
country: United States
facility: PMG Research of McFarland Clinic
state: Iowa
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Scarborough
country: United States
facility: Maine Medical Center
state: Maine
city: Bethesda
country: United States
facility: Mid-Atlantic Epilepsy and Sleep Center
state: Maryland
city: East Lansing
country: United States
facility: Michigan State University
state: Michigan
city: Golden Valley
country: United States
facility: Minneapolis Clinic of Neurology Golden Valley
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Columbia
country: United States
facility: University of Missouri Health Care
state: Missouri
city: Edison
country: United States
facility: JFK Medical Center- The Neuroscience Institute
state: New Jersey
city: Hackensack
country: United States
facility: Northeast Regional Epilepsy Group
state: New Jersey
city: New Brunswick
country: United States
facility: Saint Peter's University Hospital
state: New Jersey
city: Brooklyn
country: United States
facility: New York Presbyterian Hospital
state: New York
city: Buffalo
country: United States
facility: UBMD Neurology
state: New York
city: Woodmere
country: United States
facility: Five Towns Neuroscience Research
state: New York
city: Durham
country: United States
facility: Duke University Children's Health Center
state: North Carolina
city: Columbus
country: United States
facility: Ohio Health Research and Innovation Institute
state: Ohio
city: Toledo
country: United States
facility: University of Toledo
state: Ohio
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University Lewis Katz School of Medicine
state: Pennsylvania
city: Memphis
country: United States
facility: LeBonheur Children's Medical Center
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Austin
country: United States
facility: Child Neurology Consultants of Austin
state: Texas
city: El Paso
country: United States
facility: ANRC Research
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah / Primary Children's Hospital
state: Utah
city: Roanoke
country: United States
facility: Carilion Clinic
state: Virginia
city: Renton
country: United States
facility: Valley Medical Center
state: Washington
city: Spokane
country: United States
facility: MultiCare Institute for Research and Innovation
state: Washington
city: Heidelberg
country: Australia
facility: Austin Health
city: South Brisbane
country: Australia
facility: Children's Health Queensland Hospital
city: Gorna Oryahovitsa
country: Bulgaria
facility: MHAT Sv. Ivan Rilski Gorna Oryahovitsa EOOD
state: Veliko Tarnovo
city: Blagoevgrad
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment Puls AD
city: Ruse
country: Bulgaria
facility: UMHAT Kanev AD
city: Sofia
country: Bulgaria
facility: MHAT Lyulin EAD
city: Sofia
country: Bulgaria
facility: Acibadem City Clinic MHAT Tokuda EAD
city: Sofia
country: Bulgaria
facility: Diagnostic Consultative Center Neoclinic EAD
city: Varna
country: Bulgaria
facility: Diagnostic Consultative Center Equita EOOD
city: Veliko Tarnovo
country: Bulgaria
facility: Medical Center Medica Plus OOD
city: Praha 5
country: Czechia
facility: Fakultní nemocnice v Motole
state: Praha
city: Brno
country: Czechia
facility: Fakultni nemocnice u sv. Anny v Brne, 1. Neurologicka klinika
city: Hradec Králové
country: Czechia
facility: Nestatni zdravotnicke zarizeni, privatni ordinance neurologie
city: Ostrava-Poruba
country: Czechia
facility: Cerebrovaskularni poradna, s.r.o.
city: Ostrava-Vitkovice
country: Czechia
facility: Cerebovaskularni poradna s.r.o.
city: Praha 6
country: Czechia
facility: Forbeli s.r.o., Neurologicka ordinace
city: Rychnov Nad Kněžnou
country: Czechia
facility: Vestra Clinics, s.r.o.
city: Zlín
country: Czechia
facility: Neurologicka ambulance MUDr.Monika Zahumenska
city: Tbilisi
country: Georgia
facility: LEPL Tbilisi State Medical University Givi Zhvania Academic Clinic of Pediatry
city: Tbilisi
country: Georgia
facility: Institute of Neurology and Neuropsychology LTD
city: Berlin
country: Germany
facility: Charite - Universitätsmedizin Berlin - Sozialpädiatrisches Zentrum
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein - Campus Kiel
city: Radeberg
country: Germany
facility: Sächsisches Epilepsiezentrum Kleinwachau gGmbH
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Központ, Gyermekgyógyászati Intézet Nagyerdei krt. 98
city: Hodmezovasarhely
country: Hungary
facility: Csongrád Megyei Egészségügyi Elláto Központ Ideggyógyászati Osztály
city: Cheongju-si
country: Korea, Republic of
facility: Chungbuk National University Hospital
state: Chungcheongbuk-Do
city: Seongnam-si
country: Korea, Republic of
facility: CHA Bundang Medical Center
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: SMG-SNU Boramae Medical Center
state: Gyeonggi-Do
city: Suwon
country: Korea, Republic of
facility: Ajou University Hospital
city: Tyniec Mały
country: Poland
facility: NZOZ Poradnia Zdrowia Psychicznego Antonijczuk Boleslaw
state: Dolnoslaskie
city: Wrocław
country: Poland
facility: Centrum Medyczne Oporów
state: Dolnoslaskie
city: Ksawerow
country: Poland
facility: Centrum Opieki Zdrowotnej Orkan-Med Stec-Michalska S.J.
state: Iodzkie
city: Lublin
country: Poland
facility: Instytut Medycyny Wsi im. Witolda Chodzki w Lublinie
state: Lubelskie
city: Krakow
country: Poland
facility: Centrum Medyczne Plejady
state: Malopolskie
city: Krakow
country: Poland
facility: Wojewódzki Specjalistyczny Szpital Dziecięcy im. sw. Ludwika sw Krakowie
state: Malopolskie
city: Kraków
country: Poland
facility: Centrum Leczenia Padaczki i Migreny
state: Malopolskie
city: Warszawa
country: Poland
facility: Centrum Medyczne Warszawa Pratia s.a
state: Mazowieckie
city: Katowice
country: Poland
facility: Gornoslaskie Centrum Medyczne - Samodzielny Publiczny Szpital Kliniczny Number 7
state: Silesia
city: Katowice
country: Poland
facility: Centrum Medyczne Pratia Katowice
state: Slaskie
city: Katowice
country: Poland
facility: M.A. LEK A.M. Maciejowscy S.C Centrum Terapii SM
state: Slaskie
city: Katowice
country: Poland
facility: Niepubliczny Zaklad Opieki Zdrowotnej Novo-Med
state: Slaskie
city: Katowice
country: Poland
facility: Gyncentrum Clinic Sp. z.o.o
state: Slaskie
city: Kielce
country: Poland
facility: Niepubliczny Zakład Opieki Zdrowotnej - Centrum Neurologii Dziecięcej i Leczenia Padaczki
state: Swietokrzyskie
city: Olsztyn
country: Poland
facility: Wojewodzki Szpital Specjalistyczny w Olsztynie
state: Warminsko-Mazurskie
city: Poznań
country: Poland
facility: Clinical Research Center Spolka z Ograniczona Odpowiedzialnoscia Medic-R sp. k
state: Wielkopolskie
city: Dubnica Nad Váhom
country: Slovakia
facility: Konzílium, s.r.o
state: Trencin
city: Banská Bystrica
country: Slovakia
facility: MUDr. Beata Dupejova, neurologická ambulncia, s.r.o
city: Bardejov
country: Slovakia
facility: IN MEDIC s.r.o
city: Bratislava
country: Slovakia
facility: Narodny Ustav Detskych Chorob
city: Dolný Kubín
country: Slovakia
facility: MEDBAJ, s.r.o., Neurologicka ambulancia, Nemocnicna 1944/10
city: Krompachy
country: Slovakia
facility: NEURES, s.r.o.-Neurologická Ambulancia
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Malaga
country: Spain
facility: Hospital Regional Universitario de Malaga
city: Valencia
country: Spain
facility: Hospital Universitario La Fe
city: Dnipro
country: Ukraine
facility: Municipal Non-profit Enterprise City Clinical Hospital No.16 of Dnipro City Council, Department of Neurology
state: Dnipropetrovsk
city: Dnepropetrovsk
country: Ukraine
facility: Communal Enterprise Dnipropetrovsk Regional Clinical Hospital n.a. I.I. Mechnykov of Dnipropetrovsk Regional Council, Regional Center of Psychosomatic Disorders based on Psychoneurology Department
state: Dnipro
city: Kiev
country: Ukraine
facility: Kyiv City Psychoneurological Hospital №2
state: Kyiv
city: Odesa
country: Ukraine
facility: Municipal Non-Profit Enterprise Odesa Regional Clinical Hospital of Odesa Regional Council, Department of Cerebro-Vascular Diseases with Neurosurgery
state: Odessa
city: Uzhgorod
country: Ukraine
facility: Municipal Non-profit Enterprise Regional Clinical Center of Neurosurgery and Neurology of Zakarpattia Regional Council, Department of Neurosurgery #2
state: Zakarpattia
city: Zaporozhye
country: Ukraine
facility: Municipal Non-Profit Enterprise Zaporizhzhia Regional Clinical Hospital Of Zaporizhzhia Regional Council
state: Zaporizhzhya
city: Dnipropetrovsk
country: Ukraine
facility: Communal Enterprise Dnipropetrovsk Regional Clinical Hospital n.a. I.I. Mechnykov of Dnipropetrovsk Regional Council
city: Dnipro
country: Ukraine
facility: Communal Enterprise Regional Medical Center of Family Health of the Dnipropetrovsk Regional Council
city: Dnipro
country: Ukraine
facility: Communal Non-commercial Enterprise City Children's Clinical Hospital 6 of Dnipro City Council
city: Ivano-Frankivsk
country: Ukraine
facility: Municipal Non-profit Enterprise Prykarpattia Regional Clinical Center for Mental Health of Ivano-Frankivsk Regional Council
city: Kharkiv
country: Ukraine
facility: Communal Non-Commercial Enterprise of Kharkiv Regional Council Regional Clinical Psychiatric Hospital #3
city: Lviv
country: Ukraine
facility: Communal Non-Profit Enterprise of Lviv Regional Council Lviv Regional Clinical Hospital, Neurological Department, Antiepileptic Center
city: Odessa
country: Ukraine
facility: Communal Non-Profit Enterprise Odesa Regional Medical Centre of Mental Health Odesa Regional Council, Department #2
city: Odessa
country: Ukraine
facility: Odessa Regional Psychiatric Hospital No. 2,
city: Poltava
country: Ukraine
facility: Communal Enterprise Poltava Regional Clinical Psychiatric Hospital named after O.F. Maltsev of Poltava Regional Council
city: Ternopil
country: Ukraine
facility: Municipal Non-Profit Enterprise Ternopil Regional Clinical Psychoneurological Hospital of Ternopil Regional Council, Department of Neurology #2
city: Vinnytsya
country: Ukraine
facility: Municipal Non-profit Enterprise Vinnytsia Regional Clinical Psychoneurological Hospital named after Acad. O.I. Yushchenko of Vinnytsia Regional Council, Department of Neurology #3
Study officials:
affiliation: SK Life Science, Inc.
name: Sunita Misra, MD
role: STUDY_DIRECTOR
References:
citation: 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.