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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03678753
Recruitment Status : Recruiting
First Posted : September 20, 2018
Last Update Posted : September 19, 2019
Information provided by (Responsible Party):
SK Life Science, Inc.

Tracking Information
First Submitted Date  ICMJE September 18, 2018
First Posted Date  ICMJE September 20, 2018
Last Update Posted Date September 19, 2019
Actual Study Start Date  ICMJE September 21, 2018
Estimated Primary Completion Date November 19, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 18, 2018)
Seizure Diary [ Time Frame: 28 Days ]
Daily seizure diary that contains type and frequency of seizures
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Randomized, Double-Blind Study to Evaluate Efficacy and Safety of Cenobamate Adjunctive Therapy in PGTC Seizures
Official Title  ICMJE A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Cenobamate Adjunctive Therapy in Subjects With PGTC Seizures
Brief 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.
Detailed 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Primary Generalized Epilepsy
Intervention  ICMJE
  • Drug: Cenobamate
    12.5 mg tablet, 25 mg tablet, 50 mg tablet, 100 mg tablets, 150 mg tablets, 200 mg tablets
    Other Name: YKP3089
  • Drug: Placebo
    Matching Placebo
    Other Name: PBO
Study Arms  ICMJE
  • Experimental: Cenobamate
    Cenobamate 12.5 mg tablet once a day for two weeks, 25 mg tablet once a day for two weeks, 50 mg tablet once a day for two weeks, 100 mg tablets once a day for two weeks, 150 mg tablets once a day for two weeks and 200 mg tablets once a day for twelve weeks
    Intervention: Drug: Cenobamate
  • Placebo Comparator: Placebo
    Matching placebo
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 18, 2018)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 19, 2021
Estimated Primary Completion Date November 19, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 Informed Consent Form (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 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.
  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 AEDs with fixed dosing regimens for a minimum of 30 days prior to Visit 1 (Screening/Baseline).

    1. 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.)
    2. 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:

  1. Female subjects who are pregnant (or planning to become pregnant during the study), lactating, or breast-feeding.
  2. Subject has a history o f 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 Seizures (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 5months 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 Visit1 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 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 [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.
  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 Question 4 and/or Question 5 on the Suicidal Ideation section of the C-SSRS).
  25. Subject has more than 1 lifetime suicide attempt.
  26. 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Marc Kamin, MD 201-421-3830
Contact: Eva Pietras 201-421-3887
Listed Location Countries  ICMJE Bulgaria,   Czechia,   Hungary,   Poland,   Slovakia,   Ukraine,   United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03678753
Other Study ID Numbers  ICMJE YKP3089C025
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party SK Life Science, Inc.
Study Sponsor  ICMJE SK Life Science, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Marc Kamin, MD SK Life Science, Inc.
PRS Account SK Life Science, Inc.
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP