Safety and Pharmacokinetic Study of YKP3089 as Adjunctive Therapy in Subjects With Partial Onset Seizures

An Open Label, Multicenter, Safety and Pharmacokinetic Study of YKP3089 as Adjunctive Therapy in Subjects With Partial Onset Seizures

This is a multicenter, open label study to assess the safety and pharmacokinetics of YKP3089 as adjunctive therapy in subjects with partial onset seizures. Initially, subjects taking phenytoin or phenobarbital will be enrolled followed by additional subjects taking anti-epileptic drugs (AED) other than phenytoin and phenobarbital to further investigate long-term safety.

Study Overview

• Status: Completed
• Conditions: Partial Epilepsy
• Intervention / Treatment: Drug: YKP3089

Detailed Description

see above

• Study Type: Interventional
• Enrollment (Actual): 1345
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1093AAS
    • Hogar de Dia Casa Jesi
  • Buenos Aires, Argentina, C1093AAS
    • Instituto de Neurociencias de Fundacion Favaloro
  • Ciudad Autónoma De BuenosAires
    • Buenos Aires, Ciudad Autónoma De BuenosAires, Argentina, C1431FWO
      • Centro de Educación Médica e Investigaciones Clínicas (CEMIC)
• Australia
  • Bedford Park, Australia, 5042
    • Flinders Medical Centre
  • Box Hill, Australia, 3128
    • Eastern Health, Box Hill Hospital
  • Camperdown, Australia, 2050
    • Royal Prince Alfred Hospital
  • Chatswood, Australia, 2067
    • Strategic Health Evaluators
  • Clayton, Australia, 3168
    • Monash Medical Centre
  • Fitzroy, Australia, 3065
    • St. Vincent's Hospital Melbourne
  • Heidelberg, Australia, 3084
    • Austin Health Melbourne Brain Centre
  • Herston, Australia, 4029
    • Royal Brisbane & Women's Hospital
  • Melbourne, Australia, 3004
    • Alfred Health - The Alfred Hospital
  • Parkville, Australia, 3050
    • Melbourne Health (The Royal Melbourne Hospital)
  • Randwick, Australia, 2031
    • Prince of Wales Hospital
  • Westmead, Australia, 2145
    • Westmead Hospital
• Bulgaria
  • Blagoevgrad, Bulgaria, 2700
    • Multiprofile Hospital for Active Treatment Puls AD
  • Sofia, Bulgaria, 1431
    • University Multiprofile Hospital for Active Treatment Aleksandrovska EAD
  • Sofia, Bulgaria, 1113
    • Multiprofile Hospital for Active Treatment of Neurology and Pschiatry "Sv. Naum" EAD
  • Sofia, Bulgaria, 1142
    • First Multiprofile Hospital for Active Treatment- Sofia EAD
• Chile
  • Valdivia, Chile, 5090145
    • Hospital Base Valdivia
  • Santiago
    • La Florida, Santiago, Chile, 8260094
      • Centro Neuropsicologia LTDA.
    • Puente Alto, Santiago, Chile, 8207257
      • Complejo Asistencial Dr. Sótero del Rio
• Czechia
  • Brno, Czechia, 656 91
    • Fakultni nemocnice u sv. Anny v Brne
  • Prague, Czechia, 148 00
    • Affidea Praha s.r.o.
  • Praha 5, Czechia, 150 06
    • Fakultni nemocnice v Motole
• Germany
  • Bielefeld, Germany, 33617
    • Krankenhaus Mara gGmbH - Epilepsiezentrum Bethel
  • Bonn, Germany, 53123
    • University of Bonn, Department of Epileptology
  • Kehl, Germany, 77694
    • Epilepsiezentrum Kork
  • Mainz, Germany, 55131
    • Universitätsmedizin der Johannes Gutenberg-Universität Mainz
  • Marburg, Germany, 35043
    • Universitätsklinikum Gießen und Marburg GmbH
  • Münster, Germany, 48149
    • Universitätsklinikum Münster, Klinik fur Neurologie mit Institut fur Translationale Neurologie-Epileptologie
• Hungary
  • Budapest, Hungary, 1145
    • Országos Klinikai Idegtudományi Intézet
  • Debrecen, Hungary, 4031
    • Debreceni Egyetem Kenézy Gyula Egyetemi Kórház
  • Kecskemét, Hungary, 6000
    • Bacs Kiskun Megyei Korhaz
• Korea, Republic of
  • Busan, Korea, Republic of, 602-715
    • Dong-A University Hospital
  • Daegu, Korea, Republic of, 41931
    • Keimyung University Dongsan Hospital
  • Seoul, Korea, Republic of, 143-729
    • Konkuk University Medical Center
  • Seoul, Korea, Republic of, 110744
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital at Yonsei University Health System
  • Seoul, Korea, Republic of, 138736
    • Asan Medical Center
• Mexico
  • Ciudad de Mexico, Mexico, 03310
    • Grupo Medico Camino S.C.
  • Ciudad de Mexico, Mexico, 14200
    • Human Science Research Trials S. de R.L. de C.V.
  • Culiacán, Mexico, 80020
    • Neurociencias Estudios Clinicos S.C.
  • Monterrey, Mexico, 64060
    • Centro de Investigacion Grupo Vitamagen
  • Tlanepantla De Baz, Mexico, 54055
    • Clinical Research Institute S.C.
• Poland
  • Gdańsk, Poland, 80-803
    • COPERNICUS Podmiot Leczniczy Sp. z o.o.
  • Lódzkie
    • Łódź, Lódzkie, Poland, 90-324
      • Centrum Neurologii Krzysztof Selmaj
  • Malopolski
    • Kraków, Malopolski, Poland, 31-209
      • Centrum Leczenia Padaczki i Migreny
  • Mazowieckie
    • Warszawa, Mazowieckie, Poland, 02-952
      • Fundacja Epileptologii Prof Jerzego Majkowskiego
    • Warszawa, Mazowieckie, Poland, 02-957
      • Instytut Psychiatrii i Neurologii
  • Slaskie
    • Katowice, Slaskie, Poland, 40-650
      • Novo-Med Zielinski i wsp. Sp.J.
• Russian Federation
  • Moscow, Russian Federation, 119991
    • FSBI National Medical Research Centre of Psychiatry and Neurology n.a. V.P. Serbskiy of MoH of RF
  • Perm, Russian Federation, 614990
    • SBHI of Perm Region, Perm Territorial Clinical Hospital, Centre for Multiple Sclerosis
  • Saint Petersburg, Russian Federation, 192019
    • FSBI National Medical Research Centre of Psychiatry and Neurology n.a. V.M. Bekhterev of MoH of RF
  • Saint Petersburg, Russian Federation, 197376
    • FSBI of Science, Institute of Human Brain n.a. N.P. Bekhtereva of RAN, Laboratory of Stereotaxic Methods
  • Samara, Russian Federation, 443095
    • SBHI Samara Regional Clinical Hospital n.a. V.D. Seredavin, Neurology and Neurosurgery Departments
  • Smolensk, Russian Federation, 214019
    • SBGEI of HPE Smolensk State Medical University of MoH of RF, Chair Neurology and Neurosurgery
• Serbia
  • Belgrade, Serbia, 11000
    • Military Medical Academy
  • Belgrade, Serbia, 11000
    • Clinical Center of Serbia
  • Belgrade, Serbia, 11000
    • Institute of Mental Health
  • Kragujevac, Serbia, 34000
    • Clinical Center Kragujevac
• Spain
  • Badalona, Spain, 08916
    • Hospital Universitario Germans Trias i Pujol
  • Barcelona, Spain, 08003
    • Hospital del Mar
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Granada, Spain, 18016
    • Hospital Parque Tecnológico de la Salud
  • Madrid, Spain, 28040
    • Hospital Universitario Fundacion Jimenez Diaz
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28040
    • Hospital Universitario Clinico San Carlos
  • Madrid, Spain, 28034
    • Hospital Ruber Internacional
  • Valencia, Spain, 46026
    • Hospital Universitario y Politécnico La FE
• Sweden
  • Göteborg, Sweden, SE-41345
    • Sahlgrenska University Hospital
• Thailand
  • Muang
    • Chiang Mai, Muang, Thailand, 50200
      • Faculty of Medicine, Chiang Mai University
  • Pathumwan
    • Bangkok, Pathumwan, Thailand, 10330
      • King Chulalongkorn Memorial Hospital, Faculty of Medicine, Chulalongkorn University
• Ukraine
  • Dnipro, Ukraine, 49005
    • Municipal Institution Dnipropetrovsk Regional Clinical Hospital
  • Kharkiv, Ukraine, 61068
    • Communal Non-Commercial Enterprise of Kharkiv Regional Counsil "Regional clinical psychiatric hospital #3"
  • Kharkiv, Ukraine, 61103
    • Kharkiv Railway Clinical Hospital #1 of the Health Center Branch of JSC Ukrzaliznytsia
  • Lviv, Ukraine, 79010
    • Communal Noncommercial Enterprise of Lviv Regional Council "Lviv Regional Clinical Hospital"
  • Odesa, Ukraine
    • Municipal Non-Commercial Enterprise Odesa Regional Medical Center for Mental Health of Odessa Regional Council
  • Odesa, Ukraine
    • Municipal Non-Commercial Enterprise Odesa Regional Medical Center
  • Oleksandrivka, Ukraine, 67513
    • Municipal Institution Odesa Regional Psychiatric Hospital #2
  • Ternopil, Ukraine, 46027
    • Municipal Non-Commercial Enterprise "Ternopil Regional Clinical Psychoneurological Hospital" of Ternopil Regional Council
  • Vinnytsia, Ukraine, 21005
    • Communal Non-profit Enterprise "Vinnytsia Regional Clinical Psycho-Neurological Hospital"
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85004
      • Xen Institute
    • Phoenix, Arizona, United States, 85006
      • Banner-University Medical Center Phoenix
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Epilepsy Program
  • California
    • Anaheim, California, United States, 92806
      • Kaiser Permanente - Southern California Medical Group
    • Fresno, California, United States, 93710
      • Neuro Pain Medical Center
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
  • Colorado
    • Englewood, Colorado, United States, 80113
      • Blue Sky Neurology
  • Florida
    • Bradenton, Florida, United States, 34205
      • Bradenton Research Center Inc
    • Gulf Breeze, Florida, United States, 32561
      • NW FL Neurology Center
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Emory Brain Health Center
    • Suwanee, Georgia, United States, 30024
      • Georgia Neurology and Sleep Medicine Associates
  • Hawaii
    • Honolulu, Hawaii, United States, 96814
      • Hawaii Pacific Neuroscience
  • Idaho
    • Boise, Idaho, United States, 83702
      • Consultants In Epilepsy and Neurology PLLC
  • Iowa
    • Ames, Iowa, United States, 50010
      • MacFarland Clinic
  • Maine
    • Scarborough, Maine, United States, 04074
      • Maine Medical Partners Neurology
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • The John Hopkins University School of Medicine
    • Bethesda, Maryland, United States, 20817
      • Klein, Pavel (Private Practice)
    • Waldorf, Maryland, United States, 20603
      • Neurology Clinic PC
  • Minnesota
    • Minneapolis, Minnesota, United States, 55422
      • Minneapolis Clinic of Neurology
  • Missouri
    • Chesterfield, Missouri, United States, 63017
      • Comprehensive Epilepsy Care Center for Children and Adults PC
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Northeast Regional Epilepsy Group
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • New York, New York, United States, 10016
      • NYU Langone Medical Center
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati, Physicians Company
    • Columbus, Ohio, United States, 43214
      • Riverside Methodist Hospital
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Wexner Medical Center
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Neurological Specialty Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Epilepsy Center, Department of Neurology
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University Comprehensive Epilepsy Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Austin, Texas, United States, 78758
      • Austin Epilepsy Care Center
    • Greenville, Texas, United States, 75034
      • Hunt Regional Medical Partners
    • Temple, Texas, United States, 76508
      • Baylor Scott and White Research Institute
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia, School of Medicine
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington School of Medicine
    • Seattle, Washington, United States, 98122
      • UW Medicine, Valley Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53715
      • Dean and St. Mary's Outpatient Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

1. Male or female and greater than or equal to 18 years of age at the time of signing the informed consent. The upper age limit is 70 years inclusive.
2. Weight at least 30 kg
3. Written informed consent signed by the subject or legal guardian prior to entering the study in accordance with the International Conference on Harmonization Good Clinical Practices (ICH 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. In Germany, only the subject may sign the informed consent form in accordance with ICH guidelines.
4. A diagnosis of partial epilepsy according to the International League Against Epilepsy's Classification of Epileptic Seizures. Diagnosis should have been established by clinical history and an electroencephalogram (EEG) that is consistent with localization related epilepsy; normal interictal EEGs will be allowed provided that the subject meets the other diagnosis criterion (ie, clinical history).
5. Have uncontrolled partial seizures and require additional AED therapy despite having been treated with at least one AED within approximately the last 2 years.

6. Currently on stable antiepileptic treatment regimen:

   1. Subject must have been receiving stable doses of 1 to 3 AEDs for at least 3 weeks prior to Visit 2
   2. Vagal nerve stimulator (VNS) will not be counted as an AED; however, the parameters must remain stable for at least 4 weeks prior to baseline. The VNS must have been implanted at least 5 months prior to Visit 1.
   3. Benzodiazepines taken at least once per week during the 1 month prior to Visit 1 for epilepsy, or for anxiety or sleep disorder, will be counted as 1 AED and must be continued unchanged throughout the study. Therefore only a maximum of 2 additional approved AEDs will be allowed.
7. Computed tomography (CT) or magnetic resonance imaging (MRI) scan performed within the past 10 years that ruled out a progressive cause of epilepsy. If a CT or MRI has not been performed within the past 10 years, one must be performed prior to randomization.
8. Ability to reach subject by telephone.
9. Use of an acceptable form of birth control by female subjects of childbearing potential

Exclusion Criteria

1. History of any serious drug-induced hypersensitivity reaction (including but not limited to Stevens Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms) or any drug-related rash requiring hospitalization.
2. History of any drug-induced rash or hypersensitivity reaction.
3. History of a first degree relative with a serious cutaneous drug-induced adverse reaction.
4. History of serious systemic disease, including hepatic insufficiency, renal insufficiency, a malignant neoplasm, any disorder in which prognosis for survival is less than 3 months, or any disorder which in the judgment of the investigator will place the subject at excessive risk by participation in a controlled trial
5. Subjects taking phenytoin must not be taking phenobarbital or primidone; subjects taking phenobarbital must not be taking phenytoin or primidone
6. Subjects taking concomitant AEDs other than phenytoin or phenobarbital, must not be taking phenytoin or phenobarbital or primidone
7. Subjects with clinical evidence of phenytoin or phenobarbital toxicity
8. A history of nonepileptic or psychogenic seizures
9. Presence of only nonmotor simple partial seizures or primary generalized epilepsies
10. Presence of Lennox-Gastaut syndrome
11. Scheduled epilepsy surgery within 8 months after Visit 1
12. Subjects implanted with or planning to have implantation of deep brain stimulator
13. Pregnancy or lactation
14. Any clinically significant laboratory abnormality that in the opinion of the investigator would exclude the subject from the study
15. 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 less than 3 times the upper limit of normal (ULN)
16. An 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
17. Any clinically significant psychiatric illness, psychological, or behavioral problems that, in the opinion of the investigator, would interfere with the subject's ability to participate in the study
18. Presence of psychotic disorders and/or unstable recurrent affective disorders evident by use of antipsychotics; presence or recent history (within 6 months) of major depressive episode
19. History of alcoholism, drug abuse, or drug addiction within the past 2 years
20. Current use of felbamate with less than 18 months of continuous exposure
21. Current or recent (within the past year) use of vigabatrin or ezogabine. Subjects with a prior history of treatment with vigabatrin must have documentation showing no evidence of a vigabatrin associated clinically significant abnormality in a visual perimetry test. Subjects with a prior history of treatment with ezogabine should have no evidence of retinal abnormalities with funduscopic features similar to those seen in retinal pigment dystrophies.
22. History of status epilepticus within 3 months of Visit 1
23. Screening laboratory investigation demonstrates abnormal renal function
24. Absolute neutrophil count less than 1500/µL
25. Clinical or ECG evidence of serious cardiac disease, including ischemic heart disease, uncontrolled heart failure, and major arrhythmias, or relevant replicated changes in QT intervals (QTcF less than 340 msec or greater than 450 msec in males and greater than 470 msec in females)
26. Platelet counts lower than 80,000/µL in subjects treated with Valproic acid (divalproex sodium) (VPA)
27. A "yes" answer to Question 1 or 2 of the Columbia Suicide Severity Rating Scale (C-SSRS) (Baseline/Screening version) Ideation Section in the past 6 months or a "yes" answer to any of the Suicidal Behavior Questions in the past 2 years.
28. More than 1 lifetime suicide attempt
29. Participation in any other trials involving an investigational product or device within 30 days of screening (or longer, as required by local regulations)
30. Current use of any of the following medications: clopidogrel, fluvoxamine, amitriptyline, clomipramine, bupropion, methadone, ifosfamide, cyclophosphamide, efavirenz, fosphenytoin, ethotoin, mephenytoin, or natural progesterone (within 1 month of Visit 1)
31. History of positive antibody/antigen test for hepatitis B, hepatitis C, or HIV
32. Presence of congenital short QT syndrome
33. A history of previous exposure to YKP3089

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: YKP3089; Multiple dose	Drug: YKP3089; see above; Other Names: other anti-epileptic drug (AED)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Summary of Treatment-Emergent Adverse Events (TEAEs)	TEAEs were defined as Adverse events (AEs) with onset on or after the start of study medication, up to last dose date of study medication + 14 days or onset before study medication and worsened after starting study medication, up to last dose date of study medication + 14 days.	1 day to up to 215 weeks after first dose.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vital Signs: Meeting Abnormal Criteria (Post-Baseline Measurement)	Subjects with At Least 1 Post-Baseline Measurement Meeting Abnormal Criteria. Changes in systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, weight, and height in each safety evaluable group were small and not clinically meaningful.	1 day to up to 215 weeks after first dose.
Exposure to Study Dose - Length (Weeks)	Exposure to Study Dose was measured in Safety Population. Modal daily dose defined as the dose taken the most days during the reporting phase or study; in case of ties, modal dose was defined as the highest dose level between the two doses in the tie.	1 day to up to 215 weeks after first dose.
YKP3089 Plasma Levels (mcg/mL)	At Visit 8 and Visit 9, 2 blood samples were collected for the determination of YKP3089 plasma levels (YKP3089 and concomitant AED doses must have been stable for 2 weeks prior to these visits), at arrival and 30 minutes to 4 hours after the most recent dose. Plasma levels of phenytoin and phenobarbital were stable during the titration. The endpoint values are based on pharmacokinetic (PK) population.	Day 85 and Day 99 after first dose.
Exposure to Study Dose - Length (Months)	Exposure to Study Dose was measured in Safety Population. Modal daily dose defined as the dose taken the most days during the reporting phase or study; in case of ties, modal dose was defined as the highest dose level between the two doses in the tie.	1 day to up to 215 weeks after first dose.
Average Exposure to Study Dose	Exposure to Study Dose was measured in Safety Population. Modal daily dose defined as the dose taken the most days during the reporting phase or study; in case of ties, modal dose was defined as the highest dose level between the two doses in the tie.	1 day to up to 215 weeks after first dose.

Collaborators and Investigators

• Sponsor: SK Life Science, Inc.
• Investigators: Study Director: Marc Kamin, MD, SK Life Science, Inc.

Publications and helpful links

General Publications

• Sperling MR, Abou-Khalil B, Aboumatar S, Bhatia P, Biton V, Klein P, Krauss GL, Vossler DG, Wechsler R, Ferrari L, Grall M, Rosenfeld WE. Efficacy of cenobamate for uncontrolled focal seizures: Post hoc analysis of a Phase 3, multicenter, open-label study. Epilepsia. 2021 Dec;62(12):3005-3015. doi: 10.1111/epi.17091. Epub 2021 Oct 11.

Study record dates

Study Major Dates

• Study Start (Actual): August 3, 2016
• Primary Completion (Actual): March 31, 2021
• Study Completion (Actual): February 7, 2022

Study Registration Dates

• First Submitted: August 21, 2015
• First Submitted That Met QC Criteria: August 25, 2015
• First Posted (Estimated): August 28, 2015

Study Record Updates

• Last Update Posted (Actual): May 14, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Epilepsy; Seizures; Epilepsies, Partial; Anticonvulsants; Anticonvulsants; Cenobamate
• Other Study ID Numbers: YKP3089C021

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No