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

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

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

Study Overview

• Status: Recruiting
• Conditions: Drug Resistant Epilepsy
• Intervention / Treatment: Drug: ES-481; Drug: Placebo; Drug: Open-Label Extension Study

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Robert Niecestro, PhD; Phone Number: 917-733-5311; Email: rniecestro@estherapeutics.com

Study Locations

• Australia
  • Queensland
    • Herston, Queensland, Australia
      • Recruiting
      • Royal Brisbane and Women's Hospital
      • Contact: David Reutens
  • Victoria
    • Heidelberg, Victoria, Australia
      • Recruiting
      • Austin Hospital
      • Contact: Saul Mullen
    • Melbourne, Victoria, Australia, 3004
      • Recruiting
      • Alfred Health
      • Contact: Terence O'Brien
    • Parkville, Victoria, Australia
      • Recruiting
      • Royal Melbourne Hospital
      • Contact: John Paul Nicolo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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
2. The subject is a male or female 18 to 70 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 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
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 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

8. 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.

9. The subject is willing and able to comply with the study requirements

Exclusion Criteria:

1. Unwilling or inability to follow the procedures specified by the protocol
2. Pregnancy or breast feeding

3. 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)

4. 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
5. 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
6. 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
7. Concomitant treatment with more than four (4) AEDs
8. Evidence for a potentially progressive neurologic disorder, such as a brain tumor, multiple sclerosis or dementia
9. Planned epilepsy surgery within six months of enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo on Week 1, Week 2, Week 3 and Week 4
Experimental: ES-481	Drug: ES-481; 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
Other: Open-Label Extension Study	Drug: Open-Label Extension Study; 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).

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: ES Therapeutics Australia Pty Ltd
• Investigators: Principal Investigator: Terence O'Brien, The Alfred

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2020
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: January 13, 2021
• First Submitted That Met QC Criteria: January 14, 2021
• First Posted (Actual): January 20, 2021

Study Record Updates

• Last Update Posted (Actual): March 2, 2023
• Last Update Submitted That Met QC Criteria: March 1, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy; Drug Resistant Epilepsy
• Other Study ID Numbers: ES-481-C201

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No