| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary Generalized Tonic-Clonic Seizures |
|
| E.1.1.1 | Medical condition in easily understood language |
| Primary Generalized Tonic-Clonic Seizures |
|
| 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 |
|
| 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 therapy
compared with placebo on PGTC seizures |
|
| 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
- To evaluate the effect of cenobamate on other types of generalized
seizures
- To investigate the PK of cenobamate in subjects with PGTC seizures |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject is male or female and aged ≥18 years.
2. Written informed consent signed by the subject or legal guardian, prior to entering the study, in accordance with the International Council for 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. |
|
| 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 (e.g., tetrahydrocannabinol,
amphetamines) 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. |
|
| 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. |
|
| 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) |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints will include:
- USA and RoW only: 50% responder rate for PGTC seizures during
the Maintenance Phase.
- 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.
-Median percent change in all generalized seizure frequency per 28-day interval
during the Maintenance Phase 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 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 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 relative to baseline.
-The seizure freedom rate for PGTC seizures during the Maintenance Phase will be
calculated. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Per 28-day interval during the Maintenance Phase relative to baseline. |
|
| 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 | 8 |
| 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 |
| Ukraine |
| United States |
| Bulgaria |
| Hungary |
| Poland |
| Slovakia |
| Czechia |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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