E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 primary objective of this study is to determine the effective dose range of YKP3089 as adjunctive therapy for the treatment of partial seizures.
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E.2.2 | Secondary objectives of the trial |
The trial will also evaluate the safety and tolerability of YKP3089 in the partial epilepsy population. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female, age 18 to 70 years inclusive
2. Weight at least 40 kg
3. 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.
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 despite having been treated with at least one AED within approximately the last 2 years.
6. During the 8-week baseline period, subjects must have at least 8 partial seizures including only simple partial seizures with motor component, complex partial seizures, or secondarily generalized seizures without a seizure-free interval of greater than 25 days any time during the 8 weeks baseline. Subjects must have at least 3 of these partial seizures during each of the two consecutive 4-week segments of the baseline period.
7. Currently on stable antiepileptic treatment regimen:
a) Subject must have been receiving stable doses of 1 to 3 AEDs for at least 4 weeks prior to screening (Visit 1) to be continued unchanged throughout the study
b) 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.
c) 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. See Exclusion Criterion No. 13 for intermittent benzodiazepine rescue parameters.
8. 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.
9. Ability to reach subject by telephone.
10. Use of an acceptable form of birth control by female subjects of childbearing potential |
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E.4 | Principal exclusion criteria |
1. 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
2. A history of nonepileptic or psychogenic seizures
3. Presence of only nonmotor simple partial seizures or primary generalized epilepsies
4. History of seizure clusters (episodes lasting less than 30 minutes in which multiple seizures occur with such frequency that the initiation and completion of each individual seizure cannot be distinguished) within 3 months prior to Visit 1
5. Presence or previous history of Lennox-Gastaut syndrome
6. Scheduled epilepsy surgery within 8 months after Visit 1
7. Pregnancy or lactation
8. Any clinically significant laboratory abnormality that in the opinion of the Investigator would exclude the subject from the study
9. Evidence of significant active hepatic disease. Liver transaminases (AST or ALT) above twice the upper limit of normal or total or direct bilirubin not within normal limits
10. 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
11. 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
12. 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
13. Use of intermittent rescue benzodiazepines more than once per month (1 to 2 doses in a 24-hour period is considered 1 rescue) in the 1 month period prior to Visit 1
14. History of alcoholism, drug abuse, or drug addiction within the past 2 years
15. Current use of felbamate with less than 18 months of continuous exposure
16. Current use of diazepam, phenytoin, phenobarbital, or metabolites of these drugs (within 1 month of Visit 1)
17.Current or recent (within the past year) use of vigabatrin. 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.
18. History of status epilepticus within 3 months of Visit 1
19. History of 1 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
20. History of AED-associated rash that involved conjunctiva or mucosae or more than one maculopapular rash that required discontinuation
21. Creatinine clearance less than 50 mL/min, as calculated by the Cockcroft-Gault equation
22. Absolute neutrophil count less than 1500/μL
23. 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)
24. Platelet counts lower than 80,000/μL in subjects treated with VPA
25. 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.
26. More than 1 lifetime suicide attempt
27. Participation in any other trials involving an investigational product or device within 30 days of screening (or longer, as required by local regulations)
28. Current use of any of the following medications: clopidogrel, fluvoxamine, amitriptyline, clomipramine, bupropion, methadone, ifosfamide, cyclophosphamide, efavirenz, or natural
progesterone (within 1 month of Visit 1)
29. History of positive antibody/antigen test for hepatitis B, hepatitis C, or HIV
30. Presence of congenital short QT syndrome
31. A history of any previous exposure to YKP3089 |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoints reflect the United States Food and Drug
Administration (FDA) recommendation of percent reduction in seizure
frequency for registration which is adopted by many countries in the rest
of the world, and the European Agency for the Evaluation of Medicinal
Products (EMEA) recommendation of the responder rate for registration
in Europe, which is also adopted by Australia, New Zealand, and South
Africa.
- The primary efficacy endpoint to be evaluated for registration in the
United States and the Rest of the World is the percent change from the
pretreatment baseline phase in seizure frequency (average monthly
seizure rate per 28 days) of all simple partial motor, complex partial, or
secondarily generalized seizures compared with the double-blind
treatment phase.
- The primary efficacy endpoint to be evaluated for registration in the
countries of Europe, Australia, New Zealand, and South Africa is the
responder rate defined as a 50% or greater reduction during the
maintenance phase of the double blind period in the seizure frequency from baseline. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time point of this evaluation is after 18 weeks of treatment with study drug or placebo |
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E.5.2 | Secondary end point(s) |
- The secondary efficacy endpoint to be evaluated for registration in the
United States and the Rest of the World is the responder rate defined as
a 50% or greater reduction during the double blind period in the seizure
frequency from baseline. The responder endpoint is a binary indicator
endpoint defined as 1 if the primary endpoint is <= -50%, and 0
otherwise
- The secondary efficacy endpoint to be evaluated for registration in the
countries of Europe, Australia, New Zealand and South Africa is the
percent change from the pretreatment baseline phase in seizure
frequency (average monthly seizure rate per 28 days) of all simple
partial motor, complex partial, or secondarily generalized seizures
compared with the maintenance phase of the double-blind treatment
phase. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Time point of this evaluation is after 18 weeks of treatment with study drug or placebo |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 43 |
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 |
Australia |
Bulgaria |
Czech Republic |
France |
Germany |
Hungary |
Israel |
Korea, Republic of |
Poland |
Romania |
Serbia |
Spain |
Thailand |
Ukraine |
United Kingdom |
United States |
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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
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Visit 10 represents the end of study participation for subjects who are discontinuing after the double-blind phase.
Open-label extension phase: Until development is stopped by SK Life Science, Inc., or the product is approved for marketing, or any time at the discretion of SK Life Science, Inc. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |