Pharmacokinetic Dose-Escalation Study of Cenobamate in Pediatric Patients with Partial-Onset Seizures
- Trial ID
- 2024-514045-11-00
- Protocol
- YKP3089C039
- Sponsor
- Sk Life Science Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **pharmacokinetics** of cenobamate (YKP3089) in pediatric subjects aged 2 to less than 18 years with partial-onset seizures following single and multiple dosing. Understanding the pharmacokinetics is crucial for determining the appropriate dosing regimen, ensuring therapeutic efficacy, and minimizing potential adverse effects in this population.
The secondary objective of this study is to evaluate the safety and tolerability of cenobamate (YKP3089) following single and multiple dosing. This evaluation is essential to ensure that the treatment is not only effective but also safe for pediatric patients, providing a comprehensive understanding of its risk-benefit profile.
Participants
The clinical trial involves a total of **20 participants** diagnosed with **partial-onset seizures**. The study population consists of both male and female subjects aged between 2 to less than 18 years. Participants are required to have a diagnosis of epilepsy with partial-onset seizures, with or without secondarily generalized seizures, established at least 6 months prior to the study. The trial includes individuals who are currently on stable doses of 1 to 3 approved antiepileptic drugs (AEDs) and may also have an implanted vagal nerve stimulator or follow a ketogenic diet, provided these conditions have been stable for a specified period before the study. The selection criteria ensure that participants are capable of ingesting the study drug and that their parents or caregivers can accurately report seizure assessments. The trial population was selected based on these criteria to ensure a representative sample of pediatric subjects with the specified medical condition.
Plans and Procedures
The clinical trial is designed as a **Phase I**, open-label, pharmacokinetic, dose-escalation study to evaluate the pharmacokinetics of **cenobamate** in pediatric subjects aged 2 to less than 18 years with **partial-onset seizures**. The trial aims to assess the pharmacokinetics of cenobamate following both single and multiple dosing. The study is expected to commence recruitment on January 4, 2025, and conclude by March 31, 2026. Participants will be administered cenobamate in the form of an oral suspension, with the dosing regimen adjusted based on the pharmacokinetic findings.
The trial will include several study visits, beginning with a screening visit to confirm eligibility based on the inclusion criteria, such as a diagnosis of epilepsy with partial-onset seizures established at least six months prior to the study, and stable treatment with 1 to 3 approved antiepileptic drugs. Following the screening, participants will undergo a series of follow-up visits to monitor pharmacokinetic parameters, safety, and tolerability. These visits will include assessments such as treatment-emergent adverse events, safety laboratory tests, electrocardiograms, and physical and neurological examinations. The end-of-study visit will mark the completion of the trial for each participant, where final assessments will be conducted.
Participant involvement is expected to last until the end of the study, unless conditions arise that necessitate early termination, such as significant adverse events or non-compliance with the study protocol. The primary endpoints of the study focus on the pharmacokinetic assessment of cenobamate in plasma after single and multiple dosing. Secondary endpoints include safety and tolerability assessments, as well as exploratory efficacy evaluations through seizure frequency data collected via a seizure diary. The study is not classified as a low-intervention trial, and it is crucial that all procedures adhere to the guidelines set forth to ensure the integrity and reliability of the data collected.
Treatment
The clinical trial involves the administration of **Cenobamate**, an experimental medication, formulated as an **oral suspension** with a concentration of 10 mg/mL. The active substance, **cenobamate**, is of chemical origin and is also known by the synonym YKP3089. The pharmaceutical form is specifically designed for pediatric use, targeting subjects aged 2 to less than 18 years with partial-onset seizures. The medication is administered orally, and the study is structured to evaluate the pharmacokinetics of cenobamate through both single and multiple dosing regimens. The frequency and specific dosing schedules are determined based on the study protocol, with careful monitoring to ensure participant compliance.
In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The focus remains solely on the pharmacokinetic assessment of cenobamate in the specified pediatric population. Compliance with the dosing regimen is monitored through established clinical trial procedures to ensure accurate data collection and analysis. The trial is conducted under the sponsorship of SK Life Science, Inc., and adheres to regulatory standards for investigational medicinal products.
Efficacy
Efficacy in this clinical trial will be assessed through the collection of **seizure frequency data** as an exploratory measure. This data will be gathered using a seizure diary maintained by the participants or their caregivers. The primary focus of the trial is to evaluate the pharmacokinetics of **cenobamate** in pediatric subjects with partial-onset seizures, but the seizure frequency data will provide additional insights into the potential efficacy of the treatment. The seizure diary will serve as a tool to document the number and type of seizures experienced by the participants throughout the study period. This information will be analyzed to determine any changes in seizure frequency, which may indicate the treatment's impact on seizure control. The collection and analysis of this data will be conducted in accordance with the study protocol to ensure accuracy and reliability.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Diagnosis of epilepsy with partial-onset seizures (POS) with or without secondarily generalized seizures according to the International League Against Epilepsy’s (ILAE) Classification of Epileptic Seizures. A diagnosis should have been established at least 6 months prior to Study Day 1 by clinical history and an electroencephalogram (EEG) that is consistent with the diagnosis; normal interictal EEGs will be allowed provided that the participant meets the other diagnosis criterion (i.e., clinical history, including a history of treatment failure with at least 2 AEDs)
- Male or female subject, from age 2 to less than 18 years at the time of informed consent
- Minimum and maximum weights for cohorts IIa, IIb and III are as follows (Males and Females, 3-97 Percentile (i.e., Min-Max), Body Weight, kg). This will capture 94% of the weights of boys and girls of each age group to obtain an accurate estimate for dosing: a. cohort IIa - 16-63 kg b. cohort IIb - 13-28 kg c. cohort III - 10-20 kg
- Written informed consent signed by the subject, legal guardian, or legally authorized representative (LAR) prior to entering the study in accordance with the ICH GCP guidelines. Age-appropriate assent will be obtained for children and adolescents when the subject is cognitively able.
- Are currently being treated with stable doses of 1 to a maximum of 3 approved antiepileptic drugs (AEDs). Doses must be stable for at least 4 weeks before Study Day 1; A vagal nerve stimulator (VNS) will not be counted as one of the 3 allowable AEDs
- In the Investigator’s opinion, parents or caregivers must be able to report accurate seizure assessments during the screening and study periods and subjects must be able to ingest study drug
- Subjects with an implanted vagal nerve stimulator will be allowed if the vagal nerve stimulator was implanted at least 5 months prior to Screening and the stimulator parameters have not been changed for 30 days prior to Screening.
- Subjects following a ketogenic diet will be allowed as long as the diet has been stable for at least 30 days prior to Screening and will remain stable for the duration of the study
Exclusion Criteria
- Progressive neurological disease, including degenerative CNS diseases and progressive tumors
- Evidence of clinically significant disease or any medical condition that would compromise the subject’s ability to safely complete the study including, but not limited to, hepatic or renal failure, ischemic disease, human immunodeficiency virus (HIV) infection, active sexually transmitted disease (STD), active viral hepatitis, or malignancy
- Positive urine screen of drugs of abuse (if not due to concomitant medication, e.g., benzodiazepines as hypnotics) for Cohort 1 subjects.
- History of anoxic episodes require resuscitation within 6 months before the Screening Visit, drug or alcohol dependency or abuse within approximately the last 2 years or use of illegal recreational drugs.
- Any surgical or medical condition that may interfere with the absorption, distribution, metabolism, or excretion of the investigational product
- Consumption of any caffeine-containing products (e.g., coffee, tea, chocolate, or soda) or alcoholic beverages within 72 hours before Day 1 and 72 hours before the day of multiple dose PK sampling (Day 59 for Cohort I)
- Consumption of grapefruit or grapefruit-containing products within 72 hours before Day 1 and 72 hours before the day of multiple dose PK sampling (Day 59 for Cohort I)
- Significant clinical laboratory abnormalities, including elevation of serum AST or ALT more than 2 times the upper limit or normal (ULN) for each age group.
- Acute disease state (e.g., nausea, vomiting, fever, or diarrhea) within 7 days before Day 1
- Scheduled for surgery during the study
- Ketogenic diet or vagal nerve stimulation that has undergone alteration within 30 days of the Screening visit.
- Treatment with an investigational drug or device (other than VNS) ≤ 30 days before the Screening visit.
- Females who are breastfeeding or pregnant at Screening or Baseline or who are of reproductive age and do not agree to be abstinent or to use highly effective methods of contraception.
- Current or history of pseudo-seizures (psychogenic nonepileptic seizures) within approximately 5 years before the Screening visit
- Have a history of status epilepticus that required hospitalization during the 6 months before the Screening visit
- Have an unstable psychiatric diagnosis that may confound participants’ ability to participate in the study or that may prevent completion of the protocol-specified tests (e.g., in the judgement of the investigator, pose an appreciable risk for suicide, including suicidal behavior and ideation within 6 months before the Screening visit, current psychotic disorder, acute mania)
- Any suicidal ideation with intent or without a plan within 6 months before the Screening visit in participants aged 6 and above as determined by the CSSR-S, if able
- Evidence of clinically significant disease (e.g., cardiac, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator could affect the participant’s safety or interfere with study assessments
- Evidence of significant hematological disease; white blood cell (WBC) count equal or less than 2500/μL (2.50 1E+09/L) or an absolute neutrophil count equal or less than 1000/μL (1.00 1E+09/L)
- Clinically significant electrocardiogram (ECG) abnormality, including prolonged corrected QT interval (QTc) defined as greater than 450 msec or shortened corrected QT interval (QTc) defined as less than 350 msec
- Subject has a history or any serious drug-induced hypersensitivity reaction (including, but not limited to, Stevens Johnson syndrome, toxic epidermal necrolysis, or DRESS) or any drug-related rash requiring hospitalization.
- History or AED-associated rash that involved conjunctiva or mucosae
- History of more than one non-serious drug-related hypersensitivity reaction that required discontinuation of the medication
- Concomitant use of phenytoin and clobazam as these drugs may influence cenobamate plasma exposure. Subjects who took phenytoin or clobazam in the past must be off these drugs for at least 30 days prior to Study Day 1.
- Concomitant use of vigabatrin. Participants who took vigabatrin in the past must be off vigabatrin for at least 5 months before Study Day 1 and with documentation showing no evidence of vigabatrin-associated clinically significant abnormality in a visual perimetry test
- Concomitant use of felbamate, Subjects who took felbamate in the past must be off this drug for at least 30 days prior to Study Day 1.
- Use of potent enzyme-modifying drugs, including inhibitors of CYP enzymes (such as cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem, and HIV antivirals) and inducers of CYP enzymes (such as glucocorticoids, phenytoin, rifampin and St John`s Wort) in the previous 30 days prior to Study Day 1 of this study
- A history of intermittent use of rescue benzodiazepines (i.e., 1 to 2 doses over a 24-hour period is considered a 1-time rescue) more than twice within the 30 days prior to the Screening Visit.
- A VNS implanted less than 5 months before the Screening visit or changes in parameter less than 30 days before the Screening visit
- Presence of Familial short QT syndrome or relevant replicated QTc interval (QTcF less than 340 msec or greater than 450 msec in males and greater than 470 msec in females) on electrocardiogram (ECG)
- Previous exposure to cenobamate or sensitivity/allergy to components of the tablets or oral suspension.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Hungary | Not Recruiting | 04 Jan 2025 | 3 |
 Spain | Not Recruiting | 04 Jan 2025 | 1 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Cenobamate 10mg/mL | Test | ORAL SUSPENSION | ORAL | — | — | PRD10986003 |