Ensayos clínicos

Inclusion Criteria:

• Male and female subjects, ages 18 to 75 years, inclusive, at the time of signing the ICF.
• A diagnosis of epilepsy with focal onset (as defined in the 2017 ILAE Classification of Seizures [Fisher et al, 2017]), focal aware (except subjects with only focal aware seizures without a motor component), focal impaired awareness, and focal to bilateral tonic-clonic seizures for at least 2 years prior to signing the ICF. Diagnosis will be based on the investigator’s assessment of available clinical, radiographic, and EEG data and the review by TESC.
• A history of an average of 4 or more spontaneous and observable focal onset (as defined in the 2017 ILAE Classification of Seizures [Fisher et al, 2017]), focal aware (except subjects with only focal aware seizures without a motor component), focal impaired awareness, and focal to bilateral tonic-clonic seizures per 28-day period for at least 3 months (84 days) prior to signing the ICF.
• A minimum of 8 focal onset (as defined in the 2017 ILAE Classification of Seizures [Fisher et al, 2017]), focal aware (except subjects with only focal aware seizures without a motor component), focal impaired awareness, or focal to bilateral tonic-clonic seizures during the 8- week Baseline Period with no 21-day period free of any of these seizure types.
• Subjects who have tried and failed at least 2 appropriate AEDs in the past.
• Subjects currently taking 1 to 3 permitted AEDs (see concomitant medication exclusions) at a stable dose for 4 weeks prior to the Screening Visit. VNS, DBS, and RNS is permitted and is not considered an AED. The VNS, DBS, and RNS settings should remain stable for 4 weeks prior to the Screening Visit.
  • Note: Should a subject require a change of AED therapy/dose or VNS, DBS, or RNS settings between the Screening Visit and Visit 1, that subject should not continue in the trial at that time but must remain on the new regime for at least 4 weeks and then may repeat the screening process.
• An MRI or CT scan of the head within 10 years prior to Screening Visit to demonstrate no progressive structural abnormality. If a scan is not available, one should be conducted during the Baseline Period with a report that demonstrated no progressive structural abnormality available prior to randomization.
• BMI of 17.5 to 40.0 kg/m^2 and a total body weight > 50 kg (110 lbs).
• A female subject of childbearing potential who is sexually active with a nonsterilized male partner must agree to use a highly effective method of contraception from signing of informed consent throughout the duration of the study and for 30 days post last dose. A male subject with a pregnant or a nonpregnant partner of childbearing potential must agree to use condom during treatment and until the end of relevant systemic exposure in the male subject for 94 days following the last dose with IMP. 10 which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
• Ability, in the opinion of the investigator, to understand the nature of the trial and comply with protocol requirements, including the prescribed dosage regimens, scheduled visits, laboratory tests, and other trial procedures.

Exclusion Criteria:

• Subjects with (genetic) idiopathic generalized epilepsies or combined generalized and focal epilepsies, including a history of Lennox-Gastaut Syndrome.
• Subjects with only focal aware seizures without a motor component.
• Subjects with a history of seizures over the past 12 months that occur at such a high frequency they cannot be counted (eg, repetitive seizures, cluster seizures).
• Subjects with a history of psychogenic non-epileptic seizures within the year prior to signing the ICF.
• Subjects with a history of status epilepticus within 5 years prior to signing the ICF.
• Subjects with a history of neurosurgery for seizures less than 1 year prior to signing the ICF, or radiosurgery less than 2 years prior to signing the ICF.
• Subjects with a current history of significant cardiovascular, pulmonary, gastrointestinal, renal, hepatic, metabolic, hematological, immunological, or neurological (excluding focal onset epilepsy) disease that, in the opinion of the investigator or medical monitor, could compromise either subject safety or the results of the trial. In addition, subjects with a psychiatric illness of sufficient severity as to make them inappropriate for the trial are excluded. Medical conditions that are minor or well-controlled may be considered acceptable if the condition does not expose the subject to an undue risk of a significant AE or interfere with the assessments of safety or efficacy during the course of the trial. The medical monitor should be contacted in any instance where the investigator is uncertain regarding the stability of a subject’s medical conditions(s) and the potential impact of the condition(s) on trial participation.
• Subjects with an active CNS infection, demyelinating disease, degenerative neurological disease or any CNS disease deemed to be progressive during the course of the trial that may confound the interpretation of the trial results.
• Subjects with a history of substance or alcohol-use disorder (excluding nicotine; DSM-5 criteria) within 2 years prior to signing the ICF.
• Subjects who answer “Yes” on the C-SSRS Suicidal Ideation Item 4 (Active Suicidal Ideation with Some Intent to Act, Without Specific Plan) and whose most recent episode meeting criteria for this C-SSRS Item 4 occurred within the last 6 months, OR Subjects who answer “Yes” on the C-SSRS Suicidal Ideation Item 5 (Active Suicidal Ideation with Specific Plan and Intent) and whose most recent episode meeting criteria for this CSSRS Item 5 occurred within the last 6 months OR \Subjects who answer “Yes” on any of the 5 C-SSRS Suicidal Behavior Items (actual attempt, interrupted attempt, aborted attempt, preparatory acts, or behavior) and whose most recent episode meeting criteria for any of these 5 C-SSRS Suicidal Behavior Items occurred within the last 2 years, OR Subjects who, in the opinion of the investigator, present a serious risk of suicide.
• Subjects who test positive for human immunodeficiency virus (HIV), hepatitis B and/or or hepatitis C infection.
• Subject with a positive drug screen for illicit drugs are excluded and may not be retested or rescreened. Subjects with a positive urine drug screen resulting from use of marijuana (any cannabinoids), prescription, or over the counter medications or products that, in the investigator’s documented opinion do not signal a clinical condition that would impact the safety of the subject or interpretation of the trial results may continue evaluation for the trial following consultation and approval by the medical monitor.
• Subjects with a 12-lead ECG demonstrating either of the following: QT interval corrected for heart rate using Fridericia’s formula (QTcF) > 450 msec (average of 3 ECGs obtained at the Screening Visit assessed by central reader) QRS interval > 120 msec at the Screening Visit
• Subjects with any of the following abnormalities in clinical laboratory tests at the Screening Visit, as assessed by the central laboratory and confirmed by a single repeat measurement, if deemed necessary:
  • AST or ALT ≥ 2 x ULN;
  • Total bilirubin ≥ 1.5 x ULN.  Subjects with a history of Gilbert's Syndrome may be eligible provide the direct (conjugated) bilirubin is < ULN;
  • Females: Hemoglobin < 11 g/dL | Males: hemoglobin < 12 g/dL;
  • White blood cell (WBC) count < 3.0 x 10^9/L Neutrophil count < 2.0 x 10^9/L;
  • Platelet count < 150 x 10^9/L.
• Subjects with other abnormal laboratory test results, vital sign results, or ECG findings unless, based on the investigator’s judgment, the findings are not medically significant and would not impact the safety of the subjects or the interpretation of the trial results. The medical monitor should be contacted to discuss individual cases, as needed. Tests with exclusionary results should be repeated to ensure reproducibility of the abnormality before excluding a subject based on criteria provided in this protocol. For ECGs, 3 consecutive recordings are required and if 2 of the 3 remain exclusionary, then the subject is not eligible for the trial.
• Subjects receiving more than 3 background AEDs for their epilepsy.
• Subjects taking BZD medication chronically or who require a BZD (oral, intramuscular, or suppository) as rescue medication for epilepsy for more than 4 days on average over a 28-day -day period). During the Screening/Baseline Period, subjects requiring a BZD (oral, intramuscular, or suppository) as rescue medication for epilepsy more than 4 days on average over a 28-day period will be excluded.
• Subjects taking other prohibited medications prior to randomization or who would be likely to require the use of prohibited concomitant medications during the trial.
• Subjects taking any drug that is strong or moderate inducer/inhibitor CYP3A4 metabolism, which has the potential to alter CVL-865 exposure levels.
• Subjects taking any drug that is a sensitive P-gp and BCRP substrate.
• Vigabatrin is excluded as a concomitant AED, unless subject has been taking it for at least 2 years prior to signing the ICF and have no evidence of visual field defects on at least 2 visual field tests within 6 months of signing the ICF.
• Felbamate is excluded as a concomitant AED, unless subject has been taking it for at least 2 years prior to signing the ICF, and have acceptable hematology and liver function test values (or discontinued felbamate no less than 49 days prior to signing the ICF).
• Female subjects who are breastfeeding and/or who have a positive pregnancy test result prior to receiving IMP.
• Any condition possibly affecting drug absorption, including bowel resections, bariatric weight loss surgery, or gastrectomy (this does not include gastric banding).
• Subjects with difficulty swallowing.
• Subjects who are known to be allergic or hypersensitive to the IMP or any of its components.
• Subjects who have participated in any clinical trial within 60 days prior to signing the ICF or who have participated in more than 2 clinical trials within the year prior to signing the ICF.
• Any subject who, in the opinion of the sponsor, investigator, or medical monitor, should not participate in the trial.

Abbreviations: AE = adverse event; AED = anti-epileptic drug; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BCRP = breast cancer resistance protein; BZD = benzodiazepine; CNS = central nervous system; C-SSRS = Columbia – Suicide Severity Rating Scale; CYP = cytochrome P450; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, 5th edition; ECG = electrocardiogram; ICF = informed consent form; IMP = investigational medicinal product; P-gp = P-glycoprotein; ULN = upper limit of normal range.