Evaluation of Cenobamate as Adjunctive Therapy in Patients Aged 12 and Older with Primary Generalized Tonic-Clonic Seizures: A Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2023-506687-13-00
- Protocol
- YKP3089C025
- Sponsor
- Sk Life Science Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate the **efficacy** of adjunctive **cenobamate** at a 200 mg dose (or the adolescent equivalent) compared with placebo in subjects aged 12 years and older with **Primary Generalized Tonic-Clonic Seizures** (PGTC). This is clinically relevant as it aims to establish cenobamate as an effective treatment option for reducing the frequency and severity of PGTC seizures, which are a significant concern in epilepsy management.
Secondary objectives include:
- Evaluating the safety and tolerability of cenobamate in subjects with PGTC seizures.
- Assessing the seizure freedom rate for PGTC seizures during the Maintenance Phase and the entire double-blind treatment phase.
- Evaluating the effect of cenobamate on other types of generalized seizures.
- Investigating the pharmacokinetics (PK) of cenobamate in subjects with PGTC seizures.
Participants
The clinical trial involves a total of **88 participants** diagnosed with **Primary Generalized Tonic-Clonic Seizures** in the context of idiopathic generalized epilepsy. The study population includes both male and female subjects aged 12 years and older. Participants were selected based on specific criteria, including a stable ketogenic diet for at least three months prior to the study, and the use of 1 to 3 concomitant antiepileptic drugs with fixed dosing regimens. The trial also accommodates subjects with implanted vagal nerve or deep brain stimulators, provided the devices were implanted at least five months before the study and remain unchanged throughout its duration. The population is characterized by a vulnerable group, as it includes adolescents and individuals with a clinical diagnosis of epilepsy. Participants are required to have experienced at least five seizures in the 12 weeks preceding the trial and must have undergone routine electroencephalogram (EEG) and imaging tests to rule out progressive causes of epilepsy. The trial aims to assess the efficacy of adjunctive cenobamate compared to placebo in reducing seizure frequency.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of **cenobamate** as an adjunctive therapy in subjects with **primary generalized tonic-clonic seizures**. The trial involves multiple centers and aims to demonstrate the efficacy of a 200 mg dose of cenobamate, or the adolescent equivalent, compared to placebo. The trial is expected to run from July 4, 2023, to January 7, 2025, with the estimated end date being December 31, 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, seizure frequency, and current antiepileptic drug regimen. The inclusion criteria require subjects to be at least 12 years old, have a clinical diagnosis of primary generalized tonic-clonic seizures, and experience a minimum of five seizures in a 12-week period prior to randomization. The screening visit will also involve obtaining informed consent and conducting necessary medical evaluations, including electroencephalograms and imaging studies if not done within the specified timeframe.
Following the screening, eligible participants will enter the double-blind treatment period, where they will be randomly assigned to receive either cenobamate or a matching placebo. The trial includes a maintenance phase during which the primary efficacy endpoint will be assessed, focusing on the median percent change in seizure frequency and the responder rate for seizure reduction. Secondary endpoints will evaluate additional efficacy measures, safety outcomes, and pharmacokinetic parameters.
Participants are expected to be involved in the study for a maximum treatment period of 23 months. The trial includes regular follow-up visits to monitor safety, efficacy, and adherence to the treatment regimen. These visits will involve clinical assessments, laboratory tests, and the collection of adverse event data. The end-of-study visit will conclude the participant's involvement, with a final evaluation of their health status and study outcomes.
Conditions that may lead to early termination from the study include significant adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial is conducted in accordance with Good Clinical Practice guidelines, ensuring the safety and well-being of all participants throughout the study duration.
Treatment
The clinical trial involves the administration of **Cenobamate** in various formulations and dosages. **Cenobamate** is provided as a **film-coated tablet** in strengths of 12.5 mg, 25 mg, 50 mg, and 100 mg. The tablets are intended for **oral use**. The maximum daily dose for these formulations is 200 mg, with a total maximum dose of 32,200 mg over a treatment period of 23 weeks. The active substance, **Cenobamate**, is of chemical origin and is manufactured by SK Life Science, Inc. The sponsor product code for these formulations is YKP3089.
Additionally, **Cenobamate** is available as an **oral suspension** with a concentration of 10 mg/mL. This formulation is specifically designed for pediatric use. The maximum daily dose for the oral suspension is 3 mg/kg, with a total maximum dose of 32,200 mg over the same treatment period of 23 weeks. The oral suspension is also produced by SK Life Science, Inc., and shares the same sponsor product code, YKP3089.
The study includes a **placebo** group, which involves a placebo matching the 12.5 mg, 25 mg, 50 mg, and 100 mg **Cenobamate** tablets, as well as the 10 mg/mL **Cenobamate** oral suspension. The placebo is designed to match the appearance and administration route of the active treatments to maintain the double-blind nature of the trial. The placebo does not contain any active substance.
Efficacy
The efficacy of **cenobamate** as an adjunctive therapy in subjects with primary generalized tonic-clonic seizures will be assessed through a randomized, double-blind, placebo-controlled, multicenter study. The primary efficacy endpoints will include the median percent change from baseline in seizure frequency per 28-day interval during the double-blind treatment period for the USA and Rest of the World. For Europe, South Africa, Australia, and New Zealand, the primary endpoint will be the 50% responder rate for seizures during the Maintenance Phase, defined as achieving at least a 50% reduction in seizure frequency per 28-day interval relative to baseline.
Secondary efficacy endpoints will include 100% and 75% responder rates for seizures during the Maintenance Phase relative to baseline, and the percentage of subjects achieving a 50% reduction in all generalized seizures frequency per 28-day period during the Maintenance Phase relative to baseline. Efficacy assessments will be conducted using validated scales and patient-reported outcomes at specified intervals throughout the trial. The trial will also include secondary safety and pharmacokinetic endpoints, with adverse events, clinical laboratory results, and plasma concentrations of **cenobamate** being summarized using descriptive statistics.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subject is male or female and aged ≥12 years.
- Written informed consent signed by the subject, legal guardian, or legally authorized representative (LAR) prior to entering the study, in accordance with the International for Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. Age-appropriate assent will be obtained for adolescents. 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. As required by country-specific regulations, only the subject may sign the ICF in accordance with ICH guidelines.
- Female subjects of childbearing potential are willing to use an acceptable form of birth control.
- Subject has a clinical diagnosis of PGTC seizures (with or without other subtypes of generalized seizures) in the setting of idiopathic generalized epilepsy.
- Subject experiences at least 5 PGTC seizures in 12 weeks during the Pre-Randomization Period.
- Subject has had a routine electroencephalogram (EEG) within 5 years prior to Visit 1 (Screening/Baseline) or during the Pre-Randomization Period with electroencephalographic features consistent with idiopathic generalized epilepsy; other concomitant anomalies must be explained by adequate past medical history.
- Subject has undergone computed tomography (CT) or magnetic resonance imaging (MRI) within 10 years prior to Visit 1 (Screening/Baseline) or during the Pre-Randomization Period that ruled out a progressive cause of epilepsy.
- Subject is currently receiving 1 to a maximum of 3 concomitant antiepileptic drugs (AEDs) with fixed dosing regimens for a minimum of 30 days prior to Visit 1 (Screening/Baseline). a) Benzodiazepines (except diazepam, see Exclusion Criterion No. 7) taken at least once per week during the 30 days prior to Visit 1 (Screening/Baseline) for epilepsy, anxiety, or sleep disorder will be counted as 1 AED and the dosage must be continued unchanged throughout the study. Therefore, only a maximum of 2 additional approved AEDs will be allowed. (See Exclusion Criterion No. 10 for intermittent benzodiazepine rescue parameters.) b) Subjects receiving felbamate as a concomitant AED must meet the following criteria: i. Have a 2-year history of felbamate use and a history of a fixed dosing regimen for a minimum of 60 days prior to Visit 1 (Screening/Baseline). ii. No prior or known history of hepatotoxicity or hematologic disorder due to felbamate.
- Subject with an implanted vagal nerve or deep brain stimulator will be allowed if the stimulator was implanted at least 5 months prior to Visit 1 (Screening/Baseline) and the stimulator parameters are not changed for 30 days prior to Visit 1 and for the duration of the study.
- Subject taking a ketogenic diet will be allowed as long as the diet has been stable for at least 3 months prior to Visit 1 (Screening/Baseline) and will remain stable for the duration of the study.
Exclusion Criteria
- Female subjects who are pregnant (or planning to become pregnant during the study), lactating, or breast-feeding.
- Subject has a history of status epilepticus that required hospitalization within 12 months prior to Visit 1 (Screening/Baseline).
- Subject has PGTC seizure clusters where individual seizures cannot be counted or classified.
- Subject has a history of non-epileptic psychogenic seizures.
- Subject has a concomitant diagnosis of partial onset seizure (POS).
- Subject has a clinical diagnosis of Lennox-Gastaut syndrome.
- Subject is currently taking (within the 30 days prior to Visit 1 [Screening/Baseline]) any of the following medications: diazepam (for any reason other than as intermittent benzodiazepine rescue medication), phenytoin, mephenytoin, fosphenytoin, phenobarbital, primidone, ethotoin, clopidogrel, fluvoxamine, amitriptyline, clomipramine, bupropion, methadone, ifosfamide, cyclophosphamide, or efavirenz.
- Subject has participated in previous cenobamate clinical studies.
- Subject has a history of vigabatrin use within 5 months prior to Visit 1 (Screening/Baseline), or the subject plans to begin treatment with vigabatrin during the study. a) A subject with a history of vigabatrin use that ended more than 5 months prior to Visit 1 may be enrolled after documented evidence of no vigabatrin-associated clinically significant abnormality in an automated visual perimetry test.
- Subject has a history of intermittent use of rescue benzodiazepines 4 or more times within the 30 days prior to Visit 1 (Screening/Baseline).
- Subject has received an investigational drug or device within 30 days prior to Visit 1 (Screening/Baseline).
- Subject has a history of drug or alcohol dependency or abuse within 2 years prior to Visit 1 (Screening/Baseline).
- Subject tests positive, via urine drug screen at Visit 1 (Screening/Baseline), for illicit drugs not legalized in your state or for a drug that has not been prescribed.
- Subject has a history of any serious drug-induced hypersensitivity reaction (including, but not limited to, Stevens Johnson syndrome, toxic epidermal necrolysis, or DRESS syndrome) 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.
- Subject has evidence of clinically significant abnormalities or disease that, in the opinion of the Principal Investigator, could affect the subject's safety or conduct of the study.
- Presence of congenital short QT syndrome or relevant replicated change in QT/QTc interval less than 340 msec on ECG.
- Subject has any significant 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.
- Subject has a creatinine clearance less than 50 mL/min, as calculated by Cockcroft-Gault equation.
- Subject has an absolute neutrophil count less than 1500/μL.
- Subject has platelet count lower than 80,000/μL in subjects treated with valproate.
- Subject has a history of positive antibody/antigen test for hepatitis A, hepatitis B, hepatitis C, or HIV.
- Subject has any suicidal ideation (with intent with or without a plan) at Visit 1 (Screening/Baseline) or Visit 4 (Randomization).
- Subject has more than 1 lifetime suicide attempt.
- Subject is a staff member or immediate family member of study staff.
- Previous exposure to cenobamate or sensitivity/allergy to components of the oral suspension.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 30 Aug 2018 | 10 |
 Hungary | Not Recruiting | 30 Aug 2018 | 25 |
 Poland | Not Recruiting | 30 Aug 2018 | 14 |
 Slovakia | Not Recruiting | 30 Aug 2018 | 30 |
 Spain | Not Recruiting | 30 Aug 2018 | 5 |
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 50mg | Test | FILM-COATED TABLET | ORAL USE | 200.00 | 23 | PRD10986002 |
Cenobamate 100mg | Test | FILM-COATED TABLET | ORAL USE | 200.00 | 23 | PRD4240496 |
Cenobamate 10mg/mL | Test | ORAL SUSPENSION | ORAL USE | 3.00 | 23 | PRD10986003 |
Placebo matching with 12.5mg, 25mg, 50mg, 100mg cenobamate tablets and 10mg/mL cenobamate oral suspension unit strength | Placebo | N/A | — | — | — | N/A |
Cenobamate 25mg | Test | FILM-COATED TABLET | ORAL USE | 200.00 | 23 | PRD10986001 |
Cenobamate 12.5mg | Test | TABLET | ORAL USE | 200.00 | 23 | PRD10986000 |