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

Sponsor

SK Life Science, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03678753

Collaborator

(none)

152

Enrollment

Locations

Arms

57.9

Anticipated Duration (Months)

1.9

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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 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 of study drug, 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. 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.

Condition or Disease	Intervention/Treatment	Phase
Primary Generalized Epilepsy	Drug: Cenobamate Drug: Placebo	Phase 3

Detailed Description

This randomized, double-blind, placebo controlled trial is designed to look at safety and efficacy 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. 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.

Throughout the study, subjects will keep a diary containing the type and frequency of seizures. This will be the primary efficacy measure.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

152 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Sep 21, 2018

Anticipated Primary Completion Date :

Jun 19, 2023

Anticipated Study Completion Date :

Jul 19, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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	Drug: Cenobamate 12.5 mg tablet, 25 mg tablet, 50 mg tablet, 100 mg tablets, 150 mg tablets, 200 mg tablets Other Names: YKP3089
Placebo Comparator: Placebo Matching placebo	Drug: Placebo Matching Placebo Other Names: PBO

Arm

Intervention/Treatment

Experimental: 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

Drug: Cenobamate

12.5 mg tablet, 25 mg tablet, 50 mg tablet, 100 mg tablets, 150 mg tablets, 200 mg tablets

Other Names:

YKP3089

Placebo Comparator: Placebo

Matching placebo

Drug: Placebo

Matching Placebo

Other Names:

PBO

Outcome Measures

Primary Outcome Measures

Seizure Diary [28 Days]
Daily seizure diary that contains type and frequency of seizures

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Subject is male or female and aged ≥18 years.
Written informed consent signed by the subject or legal guardian, prior to entering the study, in accordance with the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. 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.
Female subjects of childbearing potential are willing to use an acceptable form of birth control
Subject has a clinical diagnosis of PGTC seizures (with or without other subtypes of generalized seizures) in the setting of idiopathic generalized epilepsy.
Subject experiences at least 5 PGTC seizures in 12 weeks during the Pre-Randomization Period.
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.
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.
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).
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.)
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).

No prior or known history of hepatotoxicity or hematologic disorder due to felbamate.

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.
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:

Female subjects who are pregnant (or planning to become pregnant during the study), lactating, or breast-feeding.
Subject has a history o f status epilepticus that required hospitalization within 12 months prior to Visit 1 (Screening/Baseline).
Subject has PGTC seizure clusters where individual seizures cannot be counted or classified.
Subject has a history of non-epileptic psychogenic seizures.
Subject has a concomitant diagnosis of Partial Onset Seizures (POS).
Subject has a clinical diagnosis of Lennox-Gastaut syndrome.
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.
Subject has participated in previous cenobamate clinical studies.
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 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.

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).
Subject has received an investigational drug or device within 30 days prior to Visit 1 (Screening/Baseline).
Subject has a history of drug or alcohol dependency or abuse within 2 years prior to Visit 1 (Screening/Baseline).
Subject tests positive, via urine drug screen at Visit 1 (Screening/Baseline), for illicit drugs (e.g., tetrahydrocannabinol, amphetamines) or for a drug that has not been prescribed (e.g., certain opiates).
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.
History of AED-associated rash that involved conjunctiva or mucosae.
History of more than one non-serious drug-related hypersensitivity reaction that required discontinuation of the medication.
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.
Presence of congenital short QT syndrome or relevant replicated change in QT/QTc interval less than 340 msec on ECG.
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.
Subject has a creatinine clearance less than 50 mL/min, as calculated by Cockcroft-Gault equation.
Subject has an absolute neutrophil count less than 1500/µL.
Subject has platelet count lower than 80,000/µL in subjects treated with valproate.
Subject has a history of positive antibody/antigen test for hepatitis A, hepatitis B, hepatitis C, or HIV.
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).
Subject has more than 1 lifetime suicide attempt.
Subject is a staff member or immediate family member of study staff. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Neuro Pain Medical Center	Fresno	California	United States	93710
2	Altman Clinical and Translational Research Institute	La Jolla	California	United States	92093
3	University of Colorado Hospital-Anschutz Medical Campus	Aurora	Colorado	United States	80045
4	Colorado Springs Neurological Associates	Colorado Springs	Colorado	United States	80907
5	The Neurology Group LLC	Miami	Florida	United States	33176
6	Florida Hospital Medical Group	Orlando	Florida	United States	32803
7	University of South Florida	Tampa	Florida	United States	33606
8	Hawaii Pacific Neuroscience	Honolulu	Hawaii	United States	96814
9	Consultants in Epilepsy and Neurology	Boise	Idaho	United States	83702
10	Indiana University	Indianapolis	Indiana	United States	46202
11	PMG Research of McFarland Clinic	Ames	Iowa	United States	50010
12	University of Kentucky	Lexington	Kentucky	United States	40536
13	Maine Medical Center	Scarborough	Maine	United States	04074
14	Mid-Atlantic Epilepsy and Sleep Center	Bethesda	Maryland	United States	20817
15	Michigan State University	East Lansing	Michigan	United States	48824
16	Minneapolis Clinic of Neurology Golden Valley	Golden Valley	Minnesota	United States	55422
17	JFK Medical Center- The Neuroscience Institute	Edison	New Jersey	United States	08818
18	New York Presbyterian Hospital	Brooklyn	New York	United States	11215
19	UBMD Neurology	Buffalo	New York	United States	14203
20	Five Towns Neuroscience Research	Woodmere	New York	United States	11598
21	Ohio Health Research and Innovation Institute	Columbus	Ohio	United States	43214
22	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
23	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
24	Temple University Lewis Katz School of Medicine	Philadelphia	Pennsylvania	United States	19140
25	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
26	Baylor College of Medicine	Houston	Texas	United States	77030
27	Carilion Clinic	Roanoke	Virginia	United States	24016
28	Valley Medical Center	Renton	Washington	United States	98057
29	MultiCare Institute for Research and Innovation	Spokane	Washington	United States	99204
30	MHAT Sv. Ivan Rilski Gorna Oryahovitsa EOOD	Gorna Oryahovitsa	Veliko Tarnovo	Bulgaria	5100
31	Multiprofile Hospital for Active Treatment Puls AD	Blagoevgrad		Bulgaria	2700
32	UMHAT Kanev AD	Ruse		Bulgaria	7002
33	MHAT Lyulin EAD	Sofia		Bulgaria	1336
34	Acibadem City Clinic MHAT Tokuda EAD	Sofia		Bulgaria	1407
35	Diagnostic Consultative Center Neoclinic EAD	Sofia		Bulgaria	1408
36	Diagnostic Consultative Center Equita EOOD	Varna		Bulgaria	9000
37	Medical Center Medica Plus OOD	Veliko Tarnovo		Bulgaria	5000
38	Fakultni nemocnice u sv. Anny v Brne, 1. Neurologicka klinika	Brno		Czechia	656 91
39	Nestatni zdravotnicke zarizeni, privatni ordinance neurologie	Hradec Králové		Czechia	500 03
40	Cerebrovaskularni poradna, s.r.o.	Ostrava-Poruba		Czechia	708 52
41	Cerebovaskularni poradna s.r.o.	Ostrava-Vitkovice		Czechia	703 00
42	Fakultní nemocnice v Motole	Praha 5		Czechia	150 06
43	Forbeli s.r.o., Neurologicka ordinace	Praha 6		Czechia	160 00
44	Vestra Clinics, s.r.o.	Rychnov Nad Kněžnou		Czechia	516 01
45	Neurologicka ambulance MUDr.Monika Zahumenska	Zlín		Czechia	760 01
46	Semmelweis Egyetem	Budapest		Hungary	1083
47	Csongrád Megyei Egészségügyi Elláto Központ Ideggyógyászati Osztály	Hodmezovasarhely		Hungary	6800
48	NZOZ Poradnia Zdrowia Psychicznego Antonijczuk Boleslaw	Tyniec Mały	Dolnoslaskie	Poland	55-040
49	Centrum Medyczne Oporów	Wrocław	Dolnoslaskie	Poland	52-416
50	Centrum Opieki Zdrowotnej Orkan-Med Stec-Michalska S.J.	Ksawerow	Iodzkie	Poland	95-054
51	Instytut Medycyny Wsi im. Witolda Chodzki w Lublinie	Lublin	Lubelskie	Poland	20-090
52	Centrum Leczenia Padaczki i Migreny	Kraków	Malopolskie	Poland	31-209
53	Centrum Medyczne Warszawa Pratia s.a	Warszawa	Mazowieckie	Poland	01-868
54	Gornoslaskie Centrum Medyczne - Samodzielny Publiczny Szpital Kliniczny Number 7	Katowice	Silesia	Poland	40-635
55	Centrum Medyczne Pratia Katowice	Katowice	Slaskie	Poland	40-081
56	M.A. LEK A.M. Maciejowscy S.C Centrum Terapii SM	Katowice	Slaskie	Poland	40-571
57	Niepubliczny Zaklad Opieki Zdrowotnej Novo-Med	Katowice	Slaskie	Poland	40-650
58	Gyncentrum Clinic Sp. z.o.o	Katowice	Slaskie	Poland	40-851
59	Wojewodzki Szpital Specjalistyczny w Olsztynie	Olsztyn	Warminsko-Mazurskie	Poland	10-561
60	Clinical Research Center Spolka z Ograniczona Odpowiedzialnoscia Medic-R sp. k	Poznań	Wielkopolskie	Poland	60-848
61	MUDr. Beata Dupejova, neurologická ambulncia, s.r.o	Banská Bystrica		Slovakia	974 04
62	IN MEDIC s.r.o	Bardejov		Slovakia	085 01
63	MEDBAJ, s.r.o., Neurologicka ambulancia, Nemocnicna 1944/10	Dolný Kubín		Slovakia	026 01
64	Konzílium, s.r.o	Dubnica Nad Váhom		Slovakia	018 41
65	NEURES, s.r.o.-Neurologická Ambulancia	Krompachy		Slovakia	053 42
66	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	Dnipropetrovsk	Ukraine	49027
67	Municipal Non-profit Enterprise City Clinical Hospital No.16 of Dnipro City Council, Department of Neurology	Dnipro	Dnipropetrovsk	Ukraine	49005
68	Municipal Non-Profit Enterprise Odesa Regional Clinical Hospital of Odesa Regional Council, Department of Cerebro-Vascular Diseases with Neurosurgery	Odesa	Odessa	Ukraine	65025
69	Municipal Non-profit Enterprise Regional Clinical Center of Neurosurgery and Neurology of Zakarpattia Regional Council, Department of Neurosurgery #2	Uzhgorod	Zakarpattia	Ukraine	88018
70	Municipal Non-Profit Enterprise Zaporizhzhia Regional Clinical Hospital Of Zaporizhzhia Regional Council	Zaporozhye	Zaporizhzhya	Ukraine	69600
71	Communal Enterprise Dnipropetrovsk Regional Clinical Hospital n.a. I.I. Mechnykov of Dnipropetrovsk Regional Council	Dnipropetrovsk		Ukraine	49005
72	Municipal Non-profit Enterprise Prykarpattia Regional Clinical Center for Mental Health of Ivano-Frankivsk Regional Council	Ivano-Frankivsk		Ukraine	76011
73	Communal Non-Commercial Enterprise of Kharkiv Regional Council Regional Clinical Psychiatric Hospital #3	Kharkiv		Ukraine	61068
74	Kyiv City Psychoneurological Hospital №2	Kiev		Ukraine	02660
75	Communal Non-Profit Enterprise of Lviv Regional Council Lviv Regional Clinical Hospital, Neurological Department, Antiepileptic Center	Lviv		Ukraine	79010
76	Odessa Regional Medical Academy	Odessa		Ukraine	65006
77	Communal Non-Profit Enterprise Odesa Regional Medical Centre of Mental Health Odesa Regional Council, Department #2	Odessa		Ukraine	67513
78	Communal Enterprise Poltava Regional Clinical Psychiatric Hospital named after O.F. Maltsev of Poltava Regional Council	Poltava		Ukraine	36000
79	Municipal Non-Profit Enterprise Ternopil Regional Clinical Psychoneurological Hospital of Ternopil Regional Council, Department of Neurology #2	Ternopil		Ukraine	46020
80	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	21005