A Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Cenobamate Adjunctive Therapy in Subjects with Primary Generalized Tonic-Clonic Seizures

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Sk Life Science Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

31 Jan 2019 → 27 May 2025

Decision date (initial)

2024-07-03

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

SK Life Science, Inc.

External identifiers

EU CT number

2023-506687-13-00

EudraCT number

2018-001337-41

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy, Therapy

To demonstrate the efficacy of adjunctive cenobamate 200 mg dose (or the adolescent equivalent) compared with placebo on PGTC seizures in subjects ≥ 12 years of age.

Secondary objectives 4

1. To evaluate the safety and tolerability of cenobamate in subjects with PGTC seizures
2. To evaluate the seizure freedom rate for PGTC seizures during the Maintenance Phase and during the entire double blind treatment phase
3. To evaluate the effect of cenobamate on other types of generalized seizures
4. To investigate the PK of cenobamate in subjects with PGTC seizures

Conditions and MedDRA coding

Primary Generalized Tonic-Clonic Seizures

Study design 3 periods

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-002563-PIP02-19

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Subject is male or female and aged ≥12 years.
2. 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.
3. Female subjects of childbearing potential are willing to use an acceptable form of birth control.
4. Subject has a clinical diagnosis of PGTC seizures (with or without other subtypes of generalized seizures) in the setting of idiopathic generalized epilepsy.
5. Subject experiences at least 5 PGTC seizures in 12 weeks during the Pre-Randomization Period.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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 27

1. Female subjects who are pregnant (or planning to become pregnant during the study), lactating, or breast-feeding.
2. Subject has a history of status epilepticus that required hospitalization within 12 months prior to Visit 1 (Screening/Baseline).
3. Subject has PGTC seizure clusters where individual seizures cannot be counted or classified.
4. Subject has a history of non-epileptic psychogenic seizures.
5. Subject has a concomitant diagnosis of partial onset seizure (POS).
6. Subject has a clinical diagnosis of Lennox-Gastaut syndrome.
7. 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.
8. Subject has participated in previous cenobamate clinical studies.
9. 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.
10. Subject has a history of intermittent use of rescue benzodiazepines 4 or more times within the 30 days prior to Visit 1 (Screening/Baseline).
11. Subject has received an investigational drug or device within 30 days prior to Visit 1 (Screening/Baseline).
12. Subject has a history of drug or alcohol dependency or abuse within 2 years prior to Visit 1 (Screening/Baseline).
13. 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.
14. 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.
15. History of AED-associated rash that involved conjunctiva or mucosae.
16. History of more than one non-serious drug-related hypersensitivity reaction that required discontinuation of the medication.
17. 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.
18. Presence of congenital short QT syndrome or relevant replicated change in QT/QTc interval less than 340 msec on ECG.
19. 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.
20. Subject has a creatinine clearance less than 50 mL/min, as calculated by Cockcroft-Gault equation.
21. Subject has an absolute neutrophil count less than 1500/μL.
22. Subject has platelet count lower than 80,000/μL in subjects treated with valproate.
23. Subject has a history of positive antibody/antigen test for hepatitis A, hepatitis B, hepatitis C, or HIV.
24. Subject has any suicidal ideation (with intent with or without a plan) at Visit 1 (Screening/Baseline) or Visit 4 (Randomization).
25. Subject has more than 1 lifetime suicide attempt.
26. Subject is a staff member or immediate family member of study staff.
27. Previous exposure to cenobamate or sensitivity/allergy to components of the oral suspension.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. The primary efficacy endpoint will include: 1. USA and Rest of the World (RoW): median percent change from baseline in PGTC seizure frequency per 28-day interval during the Double-blind treatment period.
2. The primary efficacy endpoint will include: 2. Europe, South Africa, Australia, and New Zealand: 50% responder rate for PGTC seizures during the Maintenance Phase. A responder is defined as a subject who achieves at least a 50% reduction in PGTC seizure frequency per 28-day interval during the Maintenance Phase relative to baseline.

Secondary endpoints 6

1. The secondary efficacy endpoints will include: 1. 100% responder rates for PGTC seizures during the Maintenance Phase relative to baseline.
2. 2. 75% responder rates for PGTC seizures during the Maintenance Phase relative to baseline.
3. 3. Percentage of subjects who achieved a 50% reduction in all generalized seizures frequency per 28-day period during the Maintenance Phase relative to baseline.
4. The secondary safety endpoints will include adverse events and concomitant medication reporting, clinical laboratory results, vital signs, electrocardiograms (ECGs), physical examinations, neurologic examinations, and Columbia Suicide Severity Rating Scale (C-SSRS) results will be summarized using descriptive statistics.
5. The secondary pharmacokinetic endpoints will include: 1. Summary of individual patients’ plasma concentrations of cenobamate at their respective doses and visits.
6. 2. Population PK analysis will be performed on data available from this study alone or integrated with data from other cenobamate studies. The population PK analysis results will be reported separately. In addition, a population PK/pharmacodynamic analysis may be conducted as a stand-alone approach for PGTC or in combination with POS data, if deemed appropriate.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Sk Life Science Inc.

Sponsor organisation

Sk Life Science Inc.

Address

461 From Road Fl 5

City

Paramus

Postcode

07652-3524

Country

United States

Scientific contact point

Organisation

Sk Life Science Inc.

Contact name

Sunita Misra, MD

Public contact point

Organisation

Sk Life Science Inc.

Contact name

Sunita Misra, MD

Third parties 9

Locations

5 EU/EEA countries · 10 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 61 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications