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

Study Overview
=================
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 other than phenytoin and phenobarbital to further investigate long-term safety.

Detailed Description
-----------------
see above

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

Conditions
-----------------
Partial Epilepsy

Intervention / Treatment
-----------------
* Drug: YKP3089


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria 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. Weight at least 30 kg Written informed consent signed by the subject or legal guardian prior to entering the study in accordance with the 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. 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). Have uncontrolled partial seizures and require additional AED therapy despite having been treated with at least one AED within approximately the last 2 years. Currently on stable antiepileptic treatment regimen: Subject must have been receiving stable doses of 1 to 3 AEDs for at least 3 weeks prior to Visit 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. 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. 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. Ability to reach subject by telephone. Use of an acceptable form of birth control by female subjects of childbearing potential Exclusion Criteria 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. History of any drug-induced rash or hypersensitivity reaction. History of a first degree relative with a serious cutaneous drug-induced adverse reaction. 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 Subjects taking phenytoin must not be taking phenobarbital or primidone; subjects taking phenobarbital must not be taking phenytoin or primidone Subjects taking concomitant AEDs other than phenytoin or phenobarbital, must not be taking phenytoin or phenobarbital or primidone Subjects with clinical evidence of phenytoin or phenobarbital toxicity A history of nonepileptic or psychogenic seizures Presence of only nonmotor simple partial seizures or primary generalized epilepsies Presence of Lennox-Gastaut syndrome Scheduled epilepsy surgery within 8 months after Visit 1 Subjects implanted with or planning to have implantation of deep brain stimulator Pregnancy or lactation Any clinically significant laboratory abnormality that in the opinion of the investigator would exclude the subject from the study 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) An active 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 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 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 History of alcoholism, drug abuse, or drug addiction within the past 2 years Current use of felbamate with less than 18 months of continuous exposure 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. History of status epilepticus within 3 months of Visit 1 Screening laboratory investigation demonstrates abnormal renal function Absolute neutrophil count less than 1500/µL 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) Platelet counts lower than 80,000/µL in subjects treated with VPA A yes answer to Question 1 or 2 of the 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. More than 1 lifetime suicide attempt Participation in any other trials involving an investigational product or device within 30 days of screening (or longer, as required by local regulations) 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) History of positive antibody/antigen test for hepatitis B, hepatitis C, or HIV Presence of congenital short QT syndrome A history of previous exposure to YKP3089

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: YKP3089<br>Multiple dose | Drug: YKP3089<br>* see above<br>* Other names: other AEDs;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the pharmacokinetics of YKP3089 and concomitant Antiepileptic Drugs (AEDs) | Change from baseline of trough plasma concentrations of YKP3089 and concomitant AEDs | 12 weeks | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | All observed or volunteered AEs and SAEs regardless of suspected causal relationship to the investigational product to be reported | 12 months. After 12 months, subjects re-evaluated and may have continued at the discretion of investigator | 
| Percentage of Participants With Laboratory Test Abnormalities (Hematology) | Hematology data will be analyzed by central laboratories. | 12 months. After 12 months, subjects re-evaluated and may have continued at the discretion of investigator | 
| Percentage of Participants With Laboratory Test Abnormalities (Chemistry) | Chemistry data will be analyzed by central laboratories | 12 months. After 12 months, subjects re-evaluated and may have continued at the discretion of investigator | 
| Percentage of Participants With Laboratory Test Abnormalities (Urinalysis) | Urinalysis data will be analyzed by central laboratories | 12 months. After 12 months, subjects re-evaluated and may have continued at the discretion of investigator | 
| Percentage of Participants With Vital Sign Results of Potential Clinical Importance | Vital signs include sitting blood pressure, respiration rate, heart rate and temperature. Potential clinical importance to be determined according to investigator clinical judgement | 12 months. After 12 months, subjects re-evaluated and may have continued at the discretion of investigator |