Evaluation of Safety and Efficacy of Cenobamate in Pediatric Patients with Partial-Onset Seizures: An Open-Label Clinical Trial
- Trial ID
- 2023-506841-52-00
- Protocol
- YKP3089C040
- Sponsor
- Sk Life Science Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and tolerability of **cenobamate** in pediatric subjects aged 2 to less than 18 years with partial-onset (focal) seizures. This is clinically relevant as it aims to ensure that the treatment is safe for use in a vulnerable population, potentially leading to improved management of seizures in children.
Secondary objectives include:
- Evaluating the efficacy of cenobamate in pediatric subjects with partial-onset (focal) seizures.
- Collecting plasma samples to support the evaluation of the pharmacokinetics (PK) of cenobamate in pediatric subjects with partial-onset (focal) seizures administered with tablets or suspension.
- Collecting plasma samples to support the evaluation of the PK/pharmacodynamics (PD) of cenobamate in pediatric subjects with partial-onset (focal) seizures.
- Assessing the acceptability and palatability of the oral suspension and tablets using a 5-point Hedonic Scale on Day 1 and Day 15.
Participants
The clinical trial involves a total of **106 participants** diagnosed with **partial-onset (focal) seizures**. The study population comprises both male and female subjects aged between 2 and less than 18 years. Participants were selected based on a confirmed diagnosis of epilepsy with partial-onset seizures, with the diagnosis established at least 12 months prior for those aged 6 to less than 18 years, and at least 1 month prior for those aged 2 to less than 6 years. The trial includes individuals who are currently on stable doses of 1 to 3 approved antiepileptic drugs, with the possibility of following a ketogenic diet, provided it has been stable for at least 30 days before the screening. Participants must have a minimum weight of 10 kilograms and have undergone brain imaging within the last 10 years to rule out progressive causes of epilepsy. The trial population is considered vulnerable, and the study aims to evaluate the safety and tolerability of cenobamate in this pediatric group.
Plans and Procedures
The clinical trial is designed to evaluate the **safety** and tolerability of **cenobamate** in pediatric subjects aged 2 to less than 18 years with **partial-onset (focal) seizures**. This open-label study will involve the administration of **cenobamate** in various formulations, including film-coated tablets and oral suspension, with a maximum treatment period of 12 months. The trial is structured as a non-randomized, open-label study, focusing on the collection of safety data and the assessment of efficacy in reducing seizure frequency. The primary endpoint is the number of participants experiencing any treatment-emergent adverse event (TEAE) and any serious adverse event (SAE) during the first year of exposure. Secondary endpoints include the percent change in seizure frequency, the number of seizure-free participants, and changes in neuropsychological assessments.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of epilepsy with partial-onset seizures, stable antiepileptic drug regimens, and a minimum weight of 10 kilograms. The screening visit will also ensure that participants have had a brain imaging study within the past 10 years to rule out progressive causes of epilepsy. Following the screening, participants will enter the treatment phase, which includes regular follow-up visits to monitor safety, efficacy, and any changes in seizure frequency or behavior. The end-of-study visit will conclude the trial, assessing the overall impact of **cenobamate** on seizure control and participant well-being.
The expected duration of participant involvement is up to 12 months, with conditions for early termination including the occurrence of significant adverse events, non-compliance with study procedures, or withdrawal of consent. Participants will be closely monitored throughout the study to ensure their safety and the integrity of the trial data. The trial is anticipated to end by June 2025, with recruitment having commenced in May 2021. The study aims to provide valuable insights into the use of **cenobamate** in managing partial-onset seizures in a pediatric population, contributing to the broader understanding of its therapeutic potential.
Treatment
The clinical trial involves the administration of **Cenobamate** in various pharmaceutical forms and dosages. **Cenobamate 50mg** is provided as a film-coated tablet. The maximum daily dose for this formulation is 50 mg, administered orally. The treatment period extends up to 12 weeks. Compliance with the dosing schedule is monitored through regular assessments.
Another formulation, **Cenobamate 10mg/mL**, is available as an oral suspension. This formulation allows for a maximum daily dose of 100 mg, also administered orally. The treatment duration is consistent with other formulations, extending up to 12 weeks. Participant adherence to the dosing regimen is evaluated periodically.
**Cenobamate 12.5mg** is administered in tablet form. The maximum daily dose for this formulation is 12.5 mg, taken orally. The treatment period is set for up to 12 weeks, with compliance monitoring in place to ensure adherence to the prescribed dosing schedule.
The **Cenobamate 25mg** formulation is provided as a film-coated tablet. Participants may receive a maximum daily dose of 25 mg, administered orally. The treatment duration is up to 12 weeks, with regular monitoring to assess participant compliance with the dosing regimen.
Lastly, **Cenobamate 100mg** is available as a film-coated tablet. The maximum daily dose for this formulation is 100 mg, administered orally. The treatment period is consistent with other formulations, extending up to 12 weeks. Participant adherence to the dosing schedule is evaluated through routine assessments.
All formulations of **Cenobamate** are chemically derived and are not designated as pediatric formulations. The trial does not include any orphan drug designations. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this study. The primary objective is to evaluate the safety and tolerability of **Cenobamate** in pediatric subjects with partial-onset (focal) seizures.
Efficacy
The efficacy of **cenobamate** in pediatric subjects with partial-onset (focal) seizures will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the safety profile, specifically the number of participants experiencing any treatment-emergent adverse event (TEAE) and any serious adverse event (SAE) during the first year of exposure. Secondary endpoints include the percent change in seizure frequency over 28 days during the treatment period and each phase of the study, the number of participants who are seizure-free, and the percentage of responders (50%, 75%, and 90% responders) during the treatment period and each phase of the study.
Additional secondary endpoints involve changes from baseline in various neuropsychological and behavioral assessments, such as the A-B neuropsychological assessment schedule (ABNAS), Child Behavior Checklist (CBCL) scores, and Lafayette Grooved Pegboard Test (LGPT) scores at the end of titration, end of maintenance, and at 52 weeks. Changes from baseline in height and weight will also be monitored. The percentage of participants with any treatment-emergent reports of suicidal ideation and behavior will be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS) during treatment, with different versions for age groups 12-18 and 6-11 years. Acceptability and palatability of the oral suspension and tablets will be evaluated using a 5-point Hedonic Scale at Visit 2 and Visit 3.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Have a diagnosis of epilepsy with partial-onset (focal) seizures (POS) with or without secondarily generalized seizures according to the International League Against Epilepsy's (ILAE) Classification of Epileptic Seizures. For participants aged 6 to less than 18 years a diagnosis should have been established at least 12 months prior to Visit 1 (Screening). For participants aged 2 to less than 6 years, a diagnosisshould have been established at least 1 month prior to Visit 1 (Screening). Diagnosis should be supported 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)
- Male or female participant, from age 2 to less than 18 years at the time of informed consent/assent (dates including informed consent in YKP3089C039)
- Have a minimum weight of 10.0 kilograms (kg) (27.0 pounds [lb])
- Have had a brain imaging (e.g., magnetic resonance imaging [MRI] scan or computed tomography (CT) within 10 years before Visit 1 (Screeining) that ruled out a progressive cause of epilepsy
- For subjects new to Study YKP3089C040 participants must have had at least 1 POS seizure during the 28-day Baseline Period. Only simple POS with motor signs, complex POS, and complex POS with secondary generalization are counted toward this inclusion for POS
- 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 to Visit 1 (Screening). A vagal nerve stimulator [VNS] will not be counted as one of the 3 allowed AEDs, but the settings should be stable for at least 4 weeks prior to Visit 1 (Screening).
- Investigator believes subject could benefit from new or continued exposure to study drug
- Subjects entering from study YKP3089C039 must continue to meet all of the inclusion criteria from the YKP3089C039 study
- Subjects receiving felbamate as a concomitant AED must meet the following criteria: a. Have a 12-month history of felbamate use and a history of a fixed dosing regimen for a minimum of 60 days prior to Visit 1 (Screening). b. No prior or known history of hepatotoxicity or hematologic disorder due to felbamate.
- Subjects following a ketogenic diet will be allowed as long as the diet has been stable for at least 30 days prior to Visit 1 (Screening) and will remain stable for the duration of the study Any potential exception to inclusion criteria allowing de minimis (clinically trivial and meaningless) variations must be approved by the medical monitor.
Exclusion Criteria
- Females who are breastfeeding or pregnant at Screening or Baseline
- Current or history of pseudo-seizures (psychogenic nonepileptic seizures) within approximately 2 years before Visit 1 (Screening).
- Have a history of status epilepticus that required hospitalization during the 6 months before Visit 1 (Screening).
- 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., significant suicide risk, including suicidal behavior and ideation within 6 months before Visit 1 (Screening), current psychotic disorder, acute mania).
- Any suicidal ideation with intent with or without a plan within 6 months before Visit 2 (i.e., answering "Yes" to questions 4 or 5 on the Suicidal Ideation section of the Columbia-Suicide Severity Rating Scale (C-SSRS) in participants aged 6 and above.
- Are scheduled and/or confirmed to have epilepsy surgery within 6 months after Visit 1 (Screening); however, those who have previously documented "failed" epilepsy surgery will be allowed.
- Evidence of clinically significant disease (e.g., cardiac, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator(s) could affect the participant's safety or interfere with the study assessments.
- Presence of only nonmotor simple partial seizures or primary generalized epilepsies.
- Evidence of moderate or severe renal insufficiency as defined by estimated glomerular filtration rates (eGFRs) of 31 to < 60 "milliliters per minute (mL/min)" and < 30 mL/min, respectively.
- Evidence of significant active hepatic disease. Stable elevation 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).
- Evidence of significant active hematological disease; white blood cell (WBC) count equal or less than 2500/μL (2.50 1E+09/liter [L]) or an absolute neutrophil count equal or less than 1000/μL (1.00 1E+09/L).
- Subjects with Familial short QT syndrome
- Clinically significant electrocardiogram (ECG) abnormality, including prolonged corrected QT interval (QTc) defined as greater than 450 milliseconds (msec) or shortened corrected QT interval (QTc) defined as less than 340 msec.
- Have a progressive central nervous system (CNS) disease, including degenerative CNS diseases and progressive tumors.
- Subject has a history of 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 of 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 vigabatrin. Participants who took vigabatrin in the past must be off vigabatrin for at least 5 months before Visit 1 (Screeining) and with documentation showing no evidence of a vigabatrin-associated clinically significant abnormality in a visual perimetry test.
- 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 once within the 30 days prior to Visit 1 (Screening).
- A VNS implanted less than 5 months before Visit 1 (Screening) or changes in parameter less than 4 weeks before Visit 1 (or thereafter during the study)
- History of or a concomitant medical condition that in the opinion of the investigator(s) would preclude the participant's participation in a clinical study or compromise the participant's ability to safely complete the study.
- Have participated in a study involving administration of an investigational drug or device within 4 weeks before Visit 1 (Screening), or within approximately 5 half-lives of the previous investigational compound, whichever is longer.
- Participants with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
- For subjects new to Study YKP3089C040 previous exposure to cenobamate or sensitivity/allergy to components of the oral suspension. Any potential exception to exclusion criteria allowing de minimis (clinically trivial and meaningless) variations must be approved by the medical monitor.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 03 May 2021 | 15 |
 Hungary | Not Recruiting | 03 May 2021 | 26 |
 Poland | Not Recruiting | 03 May 2021 | 14 |
 Spain | Not Recruiting | 03 May 2021 | 19 |
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 25mg | Test | FILM-COATED TABLET | ORAL USE | 25.00 | 12 | PRD10986001 |
Cenobamate 10mg/mL | Test | ORAL SUSPENSION | ORAL USE | 100.00 | 12 | PRD10986003 |
Cenobamate 12.5mg | Test | TABLET | ORAL USE | 12.50 | 12 | PRD10986000 |
Cenobamate 50mg | Test | FILM-COATED TABLET | ORAL USE | 50.00 | 12 | PRD10986002 |
Cenobamate 100mg | Test | FILM-COATED TABLET | ORAL USE | 100.00 | 12 | PRD4240496 |