Efficacy, Safety and Pharmacokinetics of ES-481 in Adult Patients With Drug Resistant Epilepsy

Study Overview
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Brief Summary
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This is a Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study with cross-over to Evaluate the Efficacy, Safety, and Pharmacokinetics of ES-481 in Adult Patients with Drug Resistant Epilepsy

Official Title
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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

Conditions
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Drug Resistant Epilepsy

Intervention / Treatment
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* Drug: ES-481
* Drug: Placebo
* Drug: Open-Label Extension Study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 The subject is a male or female 18 to 70 years of age, inclusive The subject must have a history of drug resistant epilepsy (as per the ILAE definition) The subject must be taking 1 to 4 antiepileptic 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 If VNS implanted, the stimulation setting must have been stable for at least four weeks prior to entering the 28-day screening period The subject/legal guardian must be able to use the seizure dairy to record seizure throughout the study The subject must experience at least four (4) countable seizures within a 28-day period. For continued enrollment into Treatment Period 1, each subject will be confirmed to have experienced at least four (4) countable seizures in the 28-day screening period The subject must have interictal epileptiform discharges and/or seizure with an average frequency of at least one (1) per hour on EEG recording. For continued enrollment into Treatment Period 1, this will be confirmed by a 24-hour EEG performed during the 28-day screening period. The subject is willing and able to comply with the study requirements Exclusion Criteria: Unwilling or inability to follow the procedures specified by the protocol Pregnancy or breast feeding Women of child-bearing potential and men who are unable or unwilling to take adequate contraceptive precautions, including one of the following: Hormonal contraception (birth control pills, injected hormones or vaginal ring) Intrauterine device Barrier methods (condom or diaphragm) combined with spermicideSurgical sterilization (hysterectomy, tubal ligation, or vasectomy) Current treatment for another significant medical disorder, such as diabetes, or heart disease or an untreated disorder, that is discovered during the 28-day screening period and might interfere with the study in the opinion of the Principal Investigator An abnormality on clinical laboratory tests, physical examination, EEG or ECG that might increase the risks associated with trial participation or investigational product administration, such as hepatic enzyme elevation greater than twice normal and/or a GFR < 60 mL/min/1.73 m2 History (within the month) of illicit drug use or alcohol dependence, and a commitment by the subject to not take the illicit drugs during the study Concomitant treatment with more than four (4) AEDs Evidence for a potentially progressive neurologic disorder, such as a brain tumor, multiple sclerosis or dementia Planned epilepsy surgery within six months of enrollment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ES-481<br> | Drug: ES-481<br>* Treatment Period Week 1 - 25 mg qd, Week 2 - 25 mg bid, Week 3 - 50 mg bid, Week 4 - 75 mg bid. Step-down and Washout Period Day 1 - 125 mg, Day 2 - 100 mg, Day 3 - 75 mg, Day 4 - 50 mg, Day 5 - 50 mg, Day 6 - 25 mg, Day 7 - 25 mg, Days 8 to 14 - 0 mg<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo on Week 1, Week 2, Week 3 and Week 4<br>|
| Other: Open-Label Extension Study<br> | Drug: Open-Label Extension Study<br>* Dosing will be at the discretion of the Investigator with a minimum dose of 25 mg/day (25 mg qd) to a maximum dose of 150 mg/day (75 mg bid).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Seizure Frequency | A change in seizure frequency and activity assessed using a patient diary and continuous 24-hour EEG monitoring (composite outcome) | Continuous and at Days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hamilton Anxiety Rating Scale (HAM-A) | To assess for changes in the HAM-A | Collected at screening, Days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70 | 
| Hamilton Depression Rating Scale (HDRS) | To assess for changes in HDRS | Collected at screening, Days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70 | 
| Adverse Events | Monitoring clinically for adverse events for both CNS and Cardiovascular events | Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70 | 
| Laboratory Assessments - Hematology | Assess changes in hematology and chemistry laboratories by blood and serum assays and analysis | Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70 | 
| Laboratory Assessments - Chemistry | Assess changes in hematology and chemistry laboratories by blood and serum assays and analysis | Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70 | 
| Pharmacokinetics (PK) - Cmax | Plasma concentration-time data will be analyzed using non compartmental methods to determine the following PK parameter: Cmax | Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70 | 
| Pharmacokinetics (PK) - Tmax | Plasma concentration-time data will be analyzed using non compartmental methods to determine the following PK parameter: Tmax | Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70 | 
| Pharmacokinetics (PK) - AUC0-t | Plasma concentration-time data will be analyzed using non compartmental methods to determine the following PK parameter: AUC0-t | Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70 | 
| Pharmacokinetics (PK) - AUC0-inf. T1/2 | Plasma concentration-time data will be analyzed using non compartmental methods to determine the following PK parameter: AUC0-inf. T1/2 | Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70 | 
| Pharmacokinetics (PK) - CL/F | Plasma concentration-time data will be analyzed using non compartmental methods to determine the following PK parameter: CL/F | Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70 | 
| Pharmacokinetics (PK) - Vz/F | Plasma concentration-time data will be analyzed using non compartmental methods to determine the following PK parameter: Vz/F | Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70 |