Cenobamate for Epilepsy

(CENOBITE Trial)

Overseen By Jong Woo Lee, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Brigham and Women's Hospital

Must be taking: Antiseizure medications

Must not be taking: Phenobarbital, Pentobarbital

Disqualifiers: Medication-related rash, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 14 days

10 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications, but it requires that you continue taking conventional antiseizure medication alongside the trial drug. If you are on medications affecting absorption, like phenobarbital, you may need to stop those.

What data supports the effectiveness of the drug Cenobamate for epilepsy?

Cenobamate has been shown to be effective in reducing seizures in adults with partial-onset epilepsy, as demonstrated in multiple studies, including pivotal phase 2 trials and a long-term open-label extension study. It has been approved in the USA for this use, indicating its effectiveness in managing seizures. ^{1 2 3 4 5}

Is cenobamate safe for humans?

Cenobamate has been studied in both healthy subjects and patients with epilepsy, showing that most side effects were mild, with only two serious adverse events reported and no deaths. It was generally well tolerated at doses up to 500 mg per day, although higher doses (600 mg) were less tolerated. ^{1 2 3 4 6}

How is the drug Cenobamate different from other epilepsy treatments?

Cenobamate is unique because it has a dual mechanism of action, blocking persistent sodium currents and enhancing the activity of the GABA-A receptor, which helps control seizures. It is also designed for once-daily dosing, making it convenient for patients. ^{1 2 3 7 8}

What is the purpose of this trial?

The CENOBITE study will be conducted as a multi-center trial involving X leading centers from the Critical Care EEG Monitoring Consortium (CCEMRC). A total of 10 patients will be recruited over a period of one year, with each patient undergoing monitored treatment regimen. Each site will obtain its own approval from their institutional review board. Data will be shared through the MGB REDCap; raw EEG files will be shared through the MGB Dropbox and analyzed at the BWH. Monitoring for the development of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, a potential adverse reaction, will be a key aspect of the study. Regular assessments, including RegiSCAR scoring (a validated scoring system for DREeSS5), daily serum cenobamate level measurements, and comprehensive lab tests, will be conducted to ensure patient safety and the effective management of any adverse reactions such as DRESS syndrome.

Research Team

Jong Woo Lee, MD, PhD

Principal Investigator

Brigham and Women's Hospital

Eligibility Criteria

This trial is for patients with nervous system disorders, epilepsy, or other neurological conditions who require intensive care. Participants will be closely monitored in a multi-center study involving leading critical care EEG monitoring sites.

Inclusion Criteria

Undergoing EEG monitoring

I experience more than one seizure per hour or have had a long seizure lasting more than 5 minutes.

I am taking medication for seizures.

Exclusion Criteria

History of medication-related rash

I am taking medication that affects how my body absorbs food or drugs.

I cannot take cenobamate due to health reasons.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a 400mg load of Cenobamate plus 100mg daily for a maximum of 14 days, with regular monitoring for DRESS syndrome and other adverse reactions

Up to 14 days

Daily monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including seizure cessation and maintenance of therapeutic levels

4 weeks

Treatment Details

Interventions

• Cenobamate

Trial Overview The CENOBITE study tests the drug Cenobamate on a small group of 10 patients to see how it affects those with severe neurological issues. Patients' reactions are tracked using advanced tools like EEG and regular lab tests.

Participant Groups

Group I: Cenobamate Experimental Treatment 1 Intervention

400mg load plus 100mg a day for maximum of 14 days

Cenobamate is already approved in United States, European Union, United Kingdom, Canada for the following indications:

Approved in United States as Xcopri for:

• Partial-onset seizures in adults

Approved in European Union as Ontozry for:

• Adjunctive treatment of focal-onset seizures with or without secondary generalization in adults with epilepsy who have not been adequately controlled despite a history of treatment with at least two anti-epileptic medications

Approved in United Kingdom as Ontozry for:

• Add-on treatment for focal-onset seizures with or without secondary generalization in adults with epilepsy who have not been adequately controlled despite a history of treatment with at least one other add-on treatment

Approved in Canada as Ontozry for:

• Adjunctive treatment of focal-onset seizures with or without secondary generalization in adults with epilepsy who have not been adequately controlled despite a history of treatment with at least two anti-epileptic medications

Who Is Running the Clinical Trial?

Brigham and Women's Hospital

Lead Sponsor

Trials

1,694

Recruited

14,790,000+

Findings from Research

Cenobamate, an investigational drug, significantly reduced the frequency of focal seizures in patients with uncontrolled epilepsy, showing a dose-dependent effect with the highest reduction observed at 400 mg (55% decrease in seizure frequency).

While cenobamate was effective, treatment-emergent adverse events were more common at higher doses, with 90% of patients in the 400 mg group experiencing side effects, indicating a need for careful monitoring at increased dosages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial. Krauss, GL., Klein, P., Brandt, C., et al.[2020]

Cenobamate (XCOPRI®) is a newly approved oral medication for treating partial-onset seizures in adults, developed by SK Life Science Inc. and Arvelle Therapeutics.

The approval was based on positive results from two pivotal phase 2 trials, highlighting its efficacy as a neurotherapeutic option for epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cenobamate: First Approval. Keam, SJ.[2020]

Cenobamate, an antiepileptic drug approved for focal seizures, demonstrated a favorable safety profile in a study involving 210 healthy subjects, with most treatment-emergent adverse events being mild and no deaths reported.

The pharmacokinetics of cenobamate support once-daily dosing, as it showed dose-proportional increases in plasma concentration and a long half-life of 30 to 76 hours, making it a convenient option for managing seizures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of Cenobamate: Results From Single and Multiple Oral Ascending-Dose Studies in Healthy Subjects. Vernillet, L., Greene, SA., Kamin, M.[2021]

In a study of 51 patients with highly refractory focal epilepsy, cenobamate demonstrated an 80.4% retention rate at the last follow-up, indicating its effectiveness in long-term treatment.

The treatment resulted in a 56.5% responder rate for focal seizures and a 63.6% responder rate for focal to bilateral tonic-clonic seizures at three months, with a manageable safety profile as 43.1% of patients reported treatment-emergent adverse events, most of which resolved.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cenobamate in patients with highly refractory focal epilepsy: A retrospective real-world study. Beltrán-Corbellini, Á., Romeral-Jiménez, M., Mayo, P., et al.[2023]

Cenobamate (CNB) demonstrated long-term efficacy in reducing seizure frequency, with a median reduction of 76.1% at 43-48 months, and 16.4% of patients achieving complete seizure freedom during this period.

The treatment was well-tolerated over the long term, with retention rates of 71% at 24 months and no new safety issues identified, although common adverse events included dizziness and fatigue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Efficacy and Safety From an Open-Label Extension of Adjunctive Cenobamate in Patients With Uncontrolled Focal Seizures. Klein, P., Aboumatar, S., Brandt, C., et al.[2022]

In a retrospective study of 45 patients, cenobamate was found to be effective for treating focal seizures, with a 60% response rate among participants, supporting its use beyond initial clinical trials.

Notably, patients with a history of drug-related rashes did not experience any rashes while on cenobamate, indicating it may be a safe option for this vulnerable group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial Real-World Experience With Cenobamate in Adolescents and Adults: A Single Center Experience. Elliott, T., Ridley-Pryor, T., Gienapp, AJ., et al.[2022]

Cenobamate, a new antiseizure medication, was found to be rapidly absorbed and well-tolerated in healthy Japanese subjects, with a maximum plasma concentration reached within 0.75 to 2.25 hours after a single oral dose.

The pharmacokinetics of cenobamate in Japanese individuals showed similar patterns to those observed in non-Japanese subjects, indicating comparable systemic exposure and safety across different populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of cenobamate, a novel antiseizure medication, in healthy Japanese, and an ethnic comparison with healthy non-Japanese. Yang, E., Sunwoo, J., Huh, KY., et al.[2022]

Cenobamate (CNB) shows promise as an effective antiseizure medication for patients with drug-resistant genetic generalized epilepsies (GGE) and combined generalized and focal epilepsies (CGFE), with a mean seizure reduction of 58% and a 70% responder rate in a retrospective review of 13 patients.

No patients experienced worsening of generalized-onset seizures while on CNB, although 77% reported side effects, indicating the need for careful management of treatment adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cenobamate in Generalized Epilepsy and Combined Generalized and Focal Epilepsy. Agashe, S., Worrell, G., Britton, J., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial. [2020]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Cenobamate: First Approval. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of Cenobamate: Results From Single and Multiple Oral Ascending-Dose Studies in Healthy Subjects. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Cenobamate in patients with highly refractory focal epilepsy: A retrospective real-world study. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Long-Term Efficacy and Safety From an Open-Label Extension of Adjunctive Cenobamate in Patients With Uncontrolled Focal Seizures. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Initial Real-World Experience With Cenobamate in Adolescents and Adults: A Single Center Experience. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of cenobamate, a novel antiseizure medication, in healthy Japanese, and an ethnic comparison with healthy non-Japanese. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Cenobamate in Generalized Epilepsy and Combined Generalized and Focal Epilepsy. [2023]