E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary Generalized Tonic-Clonic Seizures |
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E.1.1.1 | Medical condition in easily understood language |
Primary Generalized Tonic-Clonic Seizures |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10018101 |
E.1.2 | Term | Generalised tonic-clonic seizures |
E.1.2 | System Organ Class | 100000004852 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the safety and tolerability of cenobamate in subjects with PGTC seizures - To evaluate the seizure freedom rate for PGTC seizures during the Maintenance Phase and during the entire double blind treatment phase - To evaluate the effect of cenobamate on other types of generalized seizures - To investigate the PK of cenobamate in subjects with PGTC seizures |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
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. 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. |
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E.4 | Principal exclusion criteria |
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 (i.e., 1 to 2 doses over a 24-hour period is considered a 1-time rescue) 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 you region/state or for a drug that has not been prescribed (e.g., certain opiates). 14. Subject has a history of any serious drug-induced hypersensitivity reaction (including, but not limited to, Stevens Johnson syndrome, toxic epidermal necrolysis, or Drug Reaction with Eosinophilia and Systemic Symptoms [DRESS]) 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 (e.g., psychiatric, cardiac, respiratory, gastrointestinal, hepatic [AST or ALT more than 2 times the upper limit of normal (ULN), or total or direct bilirubin not more than ULN], or renal 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) (i.e., answering YES to Questions 4 and/or Question 5 on the Suicidal Ideation section of the Columbia Suicide Severity Rating Scale [C-SSRS]). 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint will include: - USA and Rest of the World (RoW): median percent change from baseline in PGTC seizure frequency per 28-day interval during the Maintenance Phase. - 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
50% reduction in PGTC seizure frequency per 28-day interval during the Maintenance Phase (Visit 9 to Visit 14) |
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints will include: - 50%, 75% and 100% responder rate for PGTC seizures during the Maintenance Phase and the Double-blind treatment period relative to baseline. - Europe, South Africa, Australia, and New Zealand only: median percent change from baseline in PGTC seizure frequency per 28-day interval during the Maintenance Phase and the Double-blind treatment period relative to baseline. -Median percent change in all generalized seizure frequency per 28-day interval during the Maintenance Phase and the Double-blind treatment period relative to baseline. -The percentage of subjects who have a 50% reduction in all generalized seizure frequency per 28-day interval during the Maintenance Phase and the Double-blind treatment period relative to baseline. -The percentage of subjects who have a 50%, 75%, 90%, and 100% reduction in seizure frequency for other types of generalized seizures including myoclonic or absence per 28-day interval during the Maintenance Phase and the Double-blind treatment period relative to baseline. - Median percent change in seizure frequency for other types of generalized seizures including myoclonic or absence seizures per 28-day interval during the Maintenance Phase and the Double-blind treatment period relative to baseline.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Per 28-day interval during the Maintenance Phase relative to baseline. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 52 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Korea, Republic of |
United States |
Poland |
Bulgaria |
Spain |
Czechia |
Germany |
Hungary |
Slovakia |
Ukraine |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 2 |