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

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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02535091

Enrollment

1345

Registered

2015-08-28

Start date

2016-08-03

Completion date

2022-02-07

Last updated

2024-05-14

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Partial Epilepsy

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

Interventions

DRUGYKP3089

see above

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 70 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Summary of Treatment-Emergent Adverse Events (TEAEs)	1 day to up to 215 weeks after first dose.	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.

Other

Measure	Time frame	Description
Vital Signs: Meeting Abnormal Criteria (Post-Baseline Measurement)	1 day to up to 215 weeks after first dose.	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.
Exposure to Study Dose - Length (Weeks)	1 day to up to 215 weeks after first 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.
YKP3089 Plasma Levels (mcg/mL)	Day 85 and Day 99 after first dose.	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.
Exposure to Study Dose - Length (Months)	1 day to up to 215 weeks after first 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.
Average Exposure to Study Dose	1 day to up to 215 weeks after first 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.

Countries

Argentina, Australia, Bulgaria, Chile, Czechia, Germany, Hungary, Mexico, Poland, Russia, Serbia, South Korea, Spain, Sweden, Thailand, Ukraine, United States

Participant flow

Pre-assignment details

Discrepancies can be found in the Protocol Enrollment number and the Participant Flow data. This discrepancy can be explained by the understanding that the Protocol Enrollment number refers to all participants that signed an informed consent form, while the Participant Flow data only takes into account participants that were dosed with at least one dose of study drug.

Participants by arm

Arm	Count
YKP3089 and Phenytoin Subjects taking phenytoin and cenobamate.	83
YKP3089 and Phenobarbital Subjects taking phenobarbital and cenobamate.	37
YKP3089 and Other AEDs Subjects taking AEDs other than phenobarbital and phenytoin and taking cenobamate.	1,220
Total	1,340

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	9	4	170
Overall Study	Entered Expanded Access Program (EAP)/Navigator	34	18	575
Overall Study	Lost to Follow-up	0	1	19
Overall Study	Other	4	3	81
Overall Study	Pregnancy	0	0	7
Overall Study	Protocol Violation	0	1	11
Overall Study	Withdrawal by Subject	14	5	121

Baseline characteristics

Characteristic	Total	YKP3089 and Phenytoin	YKP3089 and Phenobarbital	YKP3089 and Other AEDs
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	42 Participants	7 Participants	2 Participants	33 Participants
Age, Categorical Between 18 and 65 years	1298 Participants	76 Participants	35 Participants	1187 Participants
Body Mass Index (BMI)	26.92 kg/m^2 STANDARD_DEVIATION 5.982	27.69 kg/m^2 STANDARD_DEVIATION 6.126	26.78 kg/m^2 STANDARD_DEVIATION 5.28	26.87 kg/m^2 STANDARD_DEVIATION 5.993
Height	169.34 cm STANDARD_DEVIATION 10.322	170.42 cm STANDARD_DEVIATION 11.365	167.92 cm STANDARD_DEVIATION 10.064	169.31 cm STANDARD_DEVIATION 10.257
Race (NIH/OMB) American Indian or Alaska Native	59 Participants	9 Participants	0 Participants	50 Participants
Race (NIH/OMB) Asian	73 Participants	2 Participants	6 Participants	65 Participants
Race (NIH/OMB) Black or African American	47 Participants	4 Participants	1 Participants	42 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	6 Participants	1 Participants	0 Participants	5 Participants
Race (NIH/OMB) Unknown or Not Reported	90 Participants	21 Participants	2 Participants	67 Participants
Race (NIH/OMB) White	1065 Participants	46 Participants	28 Participants	991 Participants
Sex: Female, Male Female	667 Participants	28 Participants	15 Participants	624 Participants
Sex: Female, Male Male	673 Participants	55 Participants	22 Participants	596 Participants
Weight	77.30 kg STANDARD_DEVIATION 18.612	80.82 kg STANDARD_DEVIATION 21.489	75.91 kg STANDARD_DEVIATION 16.882	77.11 kg STANDARD_DEVIATION 18.442

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	2 / 83	0 / 37	8 / 1,220
other Total, other adverse events	76 / 83	35 / 37	1,104 / 1,220
serious Total, serious adverse events	15 / 83	6 / 37	217 / 1,220

Outcome results

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.