Randomized, Double-Blind Study to Evaluate Efficacy and Safety of Cenobamate Adjunctive Therapy in PGTC Seizures

  • STATUS
    Recruiting
  • End date
    Jul 19, 2023
  • participants needed
    152
  • sponsor
    SK Life Science, Inc.
Updated on 15 December 2021

Summary

This trial is intended to study the safety and effectiveness of an new anti-epileptic drug (AED) on Primary Generalized Tonic-Clonic (PGTC) Seizures. Eligible Subjects will continue to take their usual AEDs and receive either cenobamate or placebo. Subjects will have a 50% chance or receiving cenobamate or placebo (sugar pill). Subjects will initially receive 12.5 mg of cenobamate or placebo (study drug) and increase the dose every two weeks until they reach a target dose of 200 mg. Subjects will take study drug at approximately the same time in the morning (once a day) with or without food. If tolerability issues arise, dosing can be changed to evening. Also, once a subject reaches 200 mg of study drug, the dose can be decreased one time to 150 mg, if necessary. The treatment period is 22 weeks and there is a 3 week follow up period, which includes a one week decrease in study drug to 100 mg prior to stopping. Subjects who complete may be eligible for an extension study and will not have to complete the follow up period. Subjects will track their seizure types and frequency in a diary throughout the study.

Description

This randomized, double-blind, placebo controlled trial is designed to look at safety and efficacy of cenobamate adjunctive therapy as compared to placebo on PGTC seizures in subject with idiopathic generalized epilepsy. Subjects will be randomized to receive either cenobamate or placebo on a 1:1 basis. The study will have three periods, pre-randomization period where a baseline seizure frequency is established, treatment period and follow up period. The treatment period consists of a 10 week titration phase where subjects are titrated slowly until they reach the target dose and a maintenance phase. During the titration phase, subjects will receive 12.5 mg study drug, followed by 25 mg, 50 mg, 100 mg, and 150 mg study drug every two weeks. During the maintenance phase, subjects will receive the target dose of 200 mg study drug. Subjects will take their once daily dose of study drug at approximately the same in the morning with or without food. If tolerability issues arise, subjects can switch to evening dosing. There is also an option to down-titrate to 150 mg study drug, one time only. If tolerability issues continue, subjects may be discontinued. Upon completion of the maintenance phase, eligible subjects will have an opportunity to enroll in an open-label safety study. Subjects who discontinue early or do not wish to participate in this additional study will complete the three week follow up period. Subjects may receive a one week down titration to 100 mg and return for a follow up visit 2 weeks later.

Throughout the study, subjects will keep a diary containing the type and frequency of seizures. This will be the primary efficacy measure.

Details
Condition Primary Generalized Epilepsy
Treatment Placebo, Cenobamate
Clinical Study IdentifierNCT03678753
SponsorSK Life Science, Inc.
Last Modified on15 December 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Subject is male or female and aged ≥18 years
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 Informed Consent Form (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 Visit1 (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 AEDs with fixed dosing regimens for a minimum of 30 days prior to Visit 1 (Screening/Baseline)
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.)
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 o f 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 Seizures (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 5months prior to Visit 1 (Screening/Baseline), or the subject plans to begin treatment with vigabatrin during the study
A subject with a history of vigabatrin use that ended more than 5 months prior to Visit1 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 (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)
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 (e.g., tetrahydrocannabinol, amphetamines) or for a drug that has not been prescribed (e.g., certain opiates)
Subject has a history of any serious drug-induced hypersensitivity reaction (including, but not limited to, Stevens Johnson syndrome, toxic epidermal necrolysis, or DRESS) 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 (e.g., psychiatric, cardiac, respiratory, gastrointestinal, hepatic [aspartate aminotransferase (AST) or alanine aminotransferase (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
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) (i.e., answering YES to Question 4 and/or Question 5 on the Suicidal Ideation section of the C-SSRS)
Subject has more than 1 lifetime suicide attempt
Subject is a staff member or immediate family member of study staff. Any potential exception to the inclusion as well as exclusion criteria allowing de minimis (clinically trivial and meaningless) variations must be approved by the Medical Monitor
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