| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Epilepsy is a condition that affects the brain and causes repeated seizures, also known as fits. Partial-onset epilepsy begins in one area of the brain. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The objective is to evaluate the safety and pharmacokinetics of YKP3089
and concomitant AEDs when administered as adjunctive therapy for the
treatment of partial seizures. The evaluations will include:
1. Phenytoin-YKP3089 interaction
2. Phenobarbital-YKP3089 interaction
3. Long term safety of YKP3089 as adjunctive therapy in partial
onset seizures
4. Population pharmacokinetics of YKP3089 and concomitant AEDs. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female and greater than or equal to 18 years of age at the time of signing the informedconsent. The upper age limit is 70 years inclusive.
2. Weight at least 40kg
3. Written informed consent signed by the subject or legal guardian prior to entering the study inaccordance with the ICH GCP guidelines. If the written informed consent is provided by thelegal guardian because the subject is unable to do so, a written or verbal assent from thesubjectmust also be obtained. In Germany, only the subject may sign the informed consent form inaccordance with ICH guidelines.
4. A diagnosis of partial epilepsy according to the International League Against Epilepsy’sClassification of Epileptic Seizures. Diagnosis should have been established by clinical historyand an electroencephalogram (EEG) that is consistent with localization related epilepsy; normalinterictal 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 beentreated with at leastoneAED within approximately thelast 2 years.
6. Currentlyonstable antiepileptic treatment regimen:
a) Subject must have been receivingstabledoses of 1 to 3AEDs for at least 3 weeks prior to Visit2
b) Vagal nerve stimulator (VNS) or deep brain stimulator (DBS) will not be counted as an AED; however,the parameters must remain stable for at least 4 weeks prior to baseline. The VNS or DBS must have been implanted at least 5 months prior to Visit1.
c) Benzodiazepines taken at least once per week during the 1 month prior to Visit1 for epilepsy, or for anxiety or sleep disorder,will be counted as 1AED and must be continued unchanged throughout the study. Therefore only a maximum of 2 additional approved AEDs will be allowed.
7. Computed tomography (CT)ormagnetic 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 dosing.
8. Ability to reach subject by telephone.
9. Use of an acceptable form of birth control by female subjects of childbearing potential (seeSection7.5).
Any potential exception to inclusion criteria allowing de minimis (clinically trivial and meaningless) variations must be approved by the medical monitor. |
|
| E.4 | Principal 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 andsystemic symptoms) or any drug-related rash requiring hospitalization.
2. History of any drug-induced rash or hypersensitivity reaction with
documented nature of the rash or hypersensitivity reaction.
3. History of a first degree relative with a serious cutaneousdrug-inducedadverse reaction.
4. History of serious systemic disease, including hepatic insufficiency, renal insufficiency, amalignant 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 8months after Visit1
12. Subjects 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 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 ofpsychotic disorders and/or unstable recurrent affective disorders evident by use of antipsychotics; presence or recenthistory (within 6 months) of major depressive episode
19. History of alcoholism, drug abuse, or drug addiction within the past 2years
20. Current use of felbamate with less than 18 months of continuous exposure
21. Current or recent (within the past year) use of vigabatrinor ezogabine. Subjects with a priorhistory of treatment with vigabatrin must have documentation showing no evidence of avigabatrin associated clinically significant abnormality in avisual perimetry test. Subjects with a prior history of treatment with ezogabine should have no evidence of retinal abnormalities withfunduscopic features similar to those seen in retinal pigment dystrophies.
22. History ofstatus epilepticus within 3 months of Visit1
23. Screening laboratory investigation demonstrates abnormal renal function
24. Absolute neutrophilcountless than1500/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 (QTc 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 VPA
27. A "yes" answer to Question 1 or 2 of the C-SSRS (Baseline/Screeningversion)Ideation Sectionin the past 6 months or a "yes" answer to any of the Suicidal Behavior Questions in the past 2years.
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 or mephenytoin
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
Any potential exception to exclusion criteria allowing de minimis (clinically trivial and meaningless) variations must be approved by the medical monitor. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Pharmacokinetic Endpoints
Sparse PK blood samples will be collected to evaluate YKP3089 and relevant concomitant AED exposure using a population pharmacokinetics approach. This will allow for the investigation of potential effects of covariates on the pharmacokinetics of YKP3089 or other concomitant AEDs. YKP3089 and other concomitant plasma concentration data collected from this study will be pooled with relevant data from other YKP3089 clinical studies for population PK analysis.
Safety Endpoints
Safety will be assessed by the nature, frequency, and severity of treatment-emergent spontaneously reported AEs, dropouts due to AEs, overall dropout rates, and changes from baseline in vital signs, physical exams, clinical laboratory evaluations, C-SSRS and 12-lead ECGs, in YKP3089-treated subjects. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
PK blood samples will be collected per the schedule given in the Protocol section 9.4
Safety will be assessed during the entire course of the study |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Belgium |
| Bulgaria |
| Chile |
| Czech Republic |
| Germany |
| Hungary |
| Korea, Republic of |
| Mexico |
| New Zealand |
| Poland |
| Serbia |
| Spain |
| Sweden |
| Ukraine |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
After 12 months of participation in the study, subjects will be evaluated
for treatment response. Those who are benefiting from treatment with
YKP3089 may continue use of the drug at the discretion of the
investigator, until development is stopped by SK Life Science Inc or the
product is approved for marketing, or anytime at the discretion of SK Life
Science Inc. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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