Clinical trial NCT02535091: Safety and Pharmacokinetic Study of YKP3089 as Adjunctive Therapy in Subjects With Partial Onset Seizures
Official title: An Open Label, Multicenter, Safety and Pharmacokinetic Study of YKP3089 as Adjunctive Therapy in Subjects With Partial Onset Seizures
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Partial Epilepsy
Lead sponsor: SK Life Science, Inc.
Sponsor class: INDUSTRY
First posted: 2015-08-28
Enrollment: 1345
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: see above

Eligibility criteria: 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

Primary outcomes:
measure: Summary of Treatment-Emergent Adverse Events (TEAEs)
timeFrame: 1 day to up to 215 weeks after first dose.
Secondary outcomes:
Other outcomes:
measure: Vital Signs: Meeting Abnormal Criteria (Post-Baseline Measurement)
timeFrame: 1 day to up to 215 weeks after first dose.
measure: Exposure to Study Dose - Length (Weeks)
timeFrame: 1 day to up to 215 weeks after first dose.
measure: YKP3089 Plasma Levels (mcg/mL)
timeFrame: Day 85 and Day 99 after first dose.
measure: Exposure to Study Dose - Length (Months)
timeFrame: 1 day to up to 215 weeks after first dose.
measure: Average Exposure to Study Dose
timeFrame: 1 day to up to 215 weeks after first dose.
Locations:
city: Phoenix
country: United States
facility: Xen Institute
state: Arizona
city: Phoenix
country: United States
facility: Banner-University Medical Center Phoenix
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Epilepsy Program
state: Arkansas
city: Anaheim
country: United States
facility: Kaiser Permanente - Southern California Medical Group
state: California
city: Fresno
country: United States
facility: Neuro Pain Medical Center
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: Englewood
country: United States
facility: Blue Sky Neurology
state: Colorado
city: Bradenton
country: United States
facility: Bradenton Research Center Inc
state: Florida
city: Gulf Breeze
country: United States
facility: NW FL Neurology Center
state: Florida
city: Atlanta
country: United States
facility: Emory Brain Health Center
state: Georgia
city: Suwanee
country: United States
facility: Georgia Neurology and Sleep Medicine Associates
state: Georgia
city: Honolulu
country: United States
facility: Hawaii Pacific Neuroscience
state: Hawaii
city: Boise
country: United States
facility: Consultants In Epilepsy and Neurology PLLC
state: Idaho
city: Ames
country: United States
facility: MacFarland Clinic
state: Iowa
city: Scarborough
country: United States
facility: Maine Medical Partners Neurology
state: Maine
city: Baltimore
country: United States
facility: The John Hopkins University School of Medicine
state: Maryland
city: Bethesda
country: United States
facility: Klein, Pavel (Private Practice)
state: Maryland
city: Waldorf
country: United States
facility: Neurology Clinic PC
state: Maryland
city: Minneapolis
country: United States
facility: Minneapolis Clinic of Neurology
state: Minnesota
city: Chesterfield
country: United States
facility: Comprehensive Epilepsy Care Center for Children and Adults PC
state: Missouri
city: Hackensack
country: United States
facility: Northeast Regional Epilepsy Group
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati, Physicians Company
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Columbus
country: United States
facility: Riverside Methodist Hospital
state: Ohio
city: Portland
country: United States
facility: Providence Neurological Specialty Clinic
state: Oregon
city: Philadelphia
country: United States
facility: Penn Epilepsy Center, Department of Neurology
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Comprehensive Epilepsy Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Austin
country: United States
facility: Austin Epilepsy Care Center
state: Texas
city: Greenville
country: United States
facility: Hunt Regional Medical Partners
state: Texas
city: Temple
country: United States
facility: Baylor Scott and White Research Institute
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia, School of Medicine
state: Virginia
city: Seattle
country: United States
facility: University of Washington School of Medicine
state: Washington
city: Seattle
country: United States
facility: UW Medicine, Valley Medical Center
state: Washington
city: Madison
country: United States
facility: Dean and St. Mary's Outpatient Center
state: Wisconsin
city: Buenos Aires
country: Argentina
facility: Centro de Educacion Medica e Investigaciones Clinicas (CEMIC)
state: Ciudad Autónoma De BuenosAires
city: Buenos Aires
country: Argentina
facility: Hogar de Dia Casa Jesi
city: Buenos Aires
country: Argentina
facility: Instituto de Neurociencias de Fundacion Favaloro
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
city: Box Hill
country: Australia
facility: Eastern Health, Box Hill Hospital
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
city: Chatswood
country: Australia
facility: Strategic Health Evaluators
city: Clayton
country: Australia
facility: Monash Medical Centre
city: Fitzroy
country: Australia
facility: St. Vincent's Hospital Melbourne
city: Heidelberg
country: Australia
facility: Austin Health Melbourne Brain Centre
city: Herston
country: Australia
facility: Royal Brisbane & Women's Hospital
city: Melbourne
country: Australia
facility: Alfred Health - The Alfred Hospital
city: Parkville
country: Australia
facility: Melbourne Health (The Royal Melbourne Hospital)
city: Randwick
country: Australia
facility: Prince of Wales Hospital
city: Westmead
country: Australia
facility: Westmead Hospital
city: Blagoevgrad
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment Puls AD
city: Sofia
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment of Neurology and Pschiatry "Sv. Naum" EAD
city: Sofia
country: Bulgaria
facility: First Multiprofile Hospital for Active Treatment- Sofia EAD
city: Sofia
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment Aleksandrovska EAD
city: La Florida
country: Chile
facility: Centro Neuropsicologia LTDA.
state: Santiago
city: Puente Alto
country: Chile
facility: Complejo Asistencial Dr. Sotero Del Rio
state: Santiago
city: Valdivia
country: Chile
facility: Hospital Base Valdivia
city: Brno
country: Czechia
facility: Fakultni nemocnice u sv. Anny v Brne
city: Prague
country: Czechia
facility: Affidea Praha s.r.o.
city: Praha 5
country: Czechia
facility: Fakultni nemocnice v Motole
city: Bielefeld
country: Germany
facility: Krankenhaus Mara gGmbH - Epilepsiezentrum Bethel
city: Bonn
country: Germany
facility: University of Bonn, Department of Epileptology
city: Kehl
country: Germany
facility: Epilepsiezentrum Kork
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz
city: Marburg
country: Germany
facility: Universitätsklinikum Gießen und Marburg GmbH
city: Münster
country: Germany
facility: Universitätsklinikum Münster, Klinik fur Neurologie mit Institut fur Translationale Neurologie-Epileptologie
city: Budapest
country: Hungary
facility: Országos Klinikai Idegtudományi Intézet
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Kenezy Gyula Egyetemi Korhaz
city: Kecskemét
country: Hungary
facility: Bacs Kiskun Megyei Korhaz
city: Busan
country: Korea, Republic of
facility: Dong-A University Hospital
city: Daegu
country: Korea, Republic of
facility: Keimyung University Dongsan Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital at Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Konkuk University Medical Center
city: Ciudad de Mexico
country: Mexico
facility: Grupo Medico Camino S.C.
city: Ciudad de Mexico
country: Mexico
facility: Human Science Research Trials S. de R.L. de C.V.
city: Culiacán
country: Mexico
facility: Neurociencias Estudios Clinicos S.C.
city: Monterrey
country: Mexico
facility: Centro de Investigacion Grupo Vitamagen
city: Tlanepantla De Baz
country: Mexico
facility: Clinical Research Institute S.C.
city: Łódź
country: Poland
facility: Centrum Neurologii Krzysztof Selmaj
state: Lódzkie
city: Kraków
country: Poland
facility: Centrum Leczenia Padaczki i Migreny
state: Malopolski
city: Warszawa
country: Poland
facility: Fundacja Epileptologii Prof Jerzego Majkowskiego
state: Mazowieckie
city: Warszawa
country: Poland
facility: Instytut Psychiatrii i Neurologii
state: Mazowieckie
city: Katowice
country: Poland
facility: Novo-Med Zielinski i wsp. Sp.J.
state: Slaskie
city: Gdańsk
country: Poland
facility: Copernicus Podmiot Leczniczy Sp. z o.o.
city: Moscow
country: Russian Federation
facility: FSBI National Medical Research Centre of Psychiatry and Neurology n.a. V.P. Serbskiy of MoH of RF
city: Perm
country: Russian Federation
facility: SBHI of Perm Region, Perm Territorial Clinical Hospital, Centre for Multiple Sclerosis
city: Saint Petersburg
country: Russian Federation
facility: FSBI National Medical Research Centre of Psychiatry and Neurology n.a. V.M. Bekhterev of MoH of RF
city: Saint Petersburg
country: Russian Federation
facility: FSBI of Science, Institute of Human Brain n.a. N.P. Bekhtereva of RAN, Laboratory of Stereotaxic Methods
city: Samara
country: Russian Federation
facility: SBHI Samara Regional Clinical Hospital n.a. V.D. Seredavin, Neurology and Neurosurgery Departments
city: Smolensk
country: Russian Federation
facility: SBGEI of HPE Smolensk State Medical University of MoH of RF, Chair Neurology and Neurosurgery
city: Belgrade
country: Serbia
facility: Clinical Center of Serbia
city: Belgrade
country: Serbia
facility: Institute of Mental Health
city: Belgrade
country: Serbia
facility: Military Medical Academy
city: Kragujevac
country: Serbia
facility: Clinical Center Kragujevac
city: Badalona
country: Spain
facility: Hospital Universitario Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Granada
country: Spain
facility: Hospital Parque Tecnológico de la Salud
city: Madrid
country: Spain
facility: Hospital Ruber Internacional
city: Madrid
country: Spain
facility: Hospital Universitario Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario Fundacion Jimenez Diaz
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Valencia
country: Spain
facility: Hospital Universitario y Politecnico La Fe
city: Göteborg
country: Sweden
facility: Sahlgrenska University Hospital
city: Chiang Mai
country: Thailand
facility: Faculty of Medicine, Chiang Mai University
state: Muang
city: Bangkok
country: Thailand
facility: King Chulalongkorn Memorial Hospital, Faculty of Medicine, Chulalongkorn University
state: Pathumwan
city: Dnipro
country: Ukraine
facility: Municipal Institution Dnipropetrovsk Regional Clinical Hospital
city: Kharkiv
country: Ukraine
facility: Communal Non-Commercial Enterprise of Kharkiv Regional Counsil "Regional clinical psychiatric hospital #3"
city: Kharkiv
country: Ukraine
facility: Kharkiv Railway Clinical Hospital #1 of the Health Center Branch of JSC Ukrzaliznytsia
city: Lviv
country: Ukraine
facility: Communal Noncommercial Enterprise of Lviv Regional Council "Lviv Regional Clinical Hospital"
city: Odesa
country: Ukraine
facility: Municipal Non-Commercial Enterprise Odesa Regional Medical Center for Mental Health of Odessa Regional Council
city: Odesa
country: Ukraine
facility: Municipal Non-Commercial Enterprise Odesa Regional Medical Center
city: Oleksandrivka
country: Ukraine
facility: Municipal Institution Odesa Regional Psychiatric Hospital #2
city: Ternopil
country: Ukraine
facility: Municipal Non-Commercial Enterprise "Ternopil Regional Clinical Psychoneurological Hospital" of Ternopil Regional Council
city: Vinnytsia
country: Ukraine
facility: Communal Non-profit Enterprise "Vinnytsia Regional Clinical Psycho-Neurological Hospital"
Study officials:
affiliation: SK Life Science, Inc.
name: Marc Kamin, MD
role: STUDY_DIRECTOR
References:
citation: 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.