A Phase 2A, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety and Pharmacokinetics of ES-481 in Adult Patients with Drug Resistant Epilepsy.

INTERVENTION: ES‐481 will be administered as 25 mg oral gelatin capsules. The starting dose, dose administration schedule and the number of capsules of study medication (ES‐481 or Placebo) to be administered per week in each 28‐day treatment periods (Periods 1 and 2) are shown on the table below. Week 1: 25 mg daily: 1 x 25 mg gelatin capsule Days 1 to 7 in Treatment Period 1 and Days 43 to 49 in Treatment Period 2 Week 2: 25 mg twice a day: 2 x 25 mg gelatin capsules Days 8 to 14 in Treatment Period 1 and Days 50 to 56 in Treatment Period 2 Week 3: 50 mg twice a day: 4 x 25 mg gelatin capsules Days 15 to 21 in Treatment Period 1 and Days 57 to 63 in Treatment Period 2 Week 4: 75 mg twice a day: 6 x 25 mg gelatin capsules Days 22 to 28 in Treatment Period 1 and Days 64 to 70 in Treatment Period 2 In the 14‐day step‐down and washout period (following the two Treatment Periods), subjects will be washout of the medication as follows: Day 1: 125 mg: 3 x 25 mg capsules in the morning and 2 x 25 mg capsules in the evening. Day 2: 100 mg: 2 x 25 mg capsules in the morning and 2 x 25 mg capsules in the evening. Day 3: 75 mg: 2 x 25 mg capsules in the morning and 1 x 25 mg capsules in the evening. Day 4: 50 mg: 1 x 25 mg capsules in the morning and 1 x 25 mg capsules in the evening. Day 5:50 mg: 1 x 25 mg capsules in the morning and 1 x 25 mg capsules in the evening. Day 6: 25 mg: 1 x 25 mg gelatin capsule in the morning. Day 7: 25 mg: 1 x 25 mg gelatin capsule in the morning. Days 8 – 14: 0 mg: 7‐day washout period. Drug accountability will be performed on a weekly basis. CONDITION: Epilepsy; ; Epilepsy Neurological ‐ Epilepsy PRIMARY OUTCOME: A change in seizure frequency and activity assessed using a patient diary and continuous 24‐hour EEG monitoring (composite outcome)[• Seizure Frequency: will be assessed daily by the patient using patient diary.; • Seizure Activity will be assessed by Continuous 24‐Hour EEG Monitoring during the screening period and on days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70.; ] SECONDARY OUTCOME: • To assess for changes in the Hamilton Anxiety Rating Scales (HAM‐A).. ; [This outcome will be measured at screening and on study Days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70. ; ] Adverse Events ‐We will monitor clinically for adverse events for both CNS and Cardiovascular events. ; ; For CNS adverse events we will monitor clinically by both physician observation and patient self‐reporting for mood change, headache, agitation and anxiety. ; ; For Cardiovascular Adverse events we will monitor changes in blood pressure and heart rate using physician clinical assessment, patient self‐reporting along with regular assessment for changes in vital signs as well as periodic ECG for cardiac changes. ; [Adverse Events will be assessed and measured at screening and on study Days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70.] Pharmacokinetic studies ‐ The plasma concentration‐time data will be analyzed using noncompartmental methods to determine the following PK parameters: Cmax, Tmax, AUC0‐t, AUC0‐inf, T½, CL/F and Vz/F. Additional PK parameters may be calculated as data permit.[Plasma samples will be drawn at screening and on study Days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70 to estimate pharmacokinetic parameters. ; ] To assess for changes in the Hamilton Depression Rating Scale (HDRS).[This outcome will be measured at screening and on study Days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70.] 2. The subject is a male or female 18 to 65 years of age, inclusive 3. The subject must have a history of drug resistant epilepsy (as per the ILAE definition) 4. The subject must be taking 1 to 4 anti‐epileptic drugs (AED) and must be on a stable dose of the AEDs for at least four (4) weeks prior to entering the 28‐day screening period ; ] To Assess changes in hematology and chemistry laboratories by blood and serum assays and analysis.[This outcome will be measured at screening and on study Days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70. INCLUSION CRITERIA: 1. The subject/legal guardian must be able to understand and sign the Human Research Ethics Committee‐approved written Informed Consent Form (ICF) and privacy language as per national regulations (e.g., HREC and TGA requirement in Australia) prior to any study‐related procedures being performed. 5. If VNS implanted, the stimulation setting must have been stable for at least four weeks prior to entering the 28‐day screening period 6. The subject/legal guardian must be able to use the seizure dairy to record seizure throughout the study 7. The subject must experience at least four (4) countable seizures within a