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

Partial Epilepsy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02535091
• Other study ID #: YKP3089C021
• Status: Completed
• Phase: Phase 3
• Start date: August 3, 2016
• Est. completion date: February 7, 2022

Study information

• Verified date: April 2024
• Source: SK Life Science, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

see above

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1345
• Est. completion date: February 7, 2022
• Est. primary completion date: March 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Epilepsies, Partial
• Partial Epilepsy
• Seizures

Intervention

Drug:
• YKP3089
see above

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
SK Life Science, Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Bulgaria,  Chile,  Czechia,  Germany,  Hungary,  Korea, Republic of,  Mexico,  Poland,  Russian Federation,  Serbia,  Spain,  Sweden,  Thailand,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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.
Other	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.
Other	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.
Other	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.
Other	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.
Primary	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.