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

Drug Resistant Epilepsy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04714996
• Other study ID #: ES-481-C201
• Status: Recruiting
• Phase: Phase 2
• Start date: October 30, 2020
• Est. completion date: December 2023

Study information

• Verified date: March 2023
• Source: ES Therapeutics Australia Pty Ltd
• Contact: Robert Niecestro, PhD
• Phone: 917-733-5311
• Email: rniecestro[@]estherapeutics.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 24
• Est. completion date: December 2023
• Est. primary completion date: December 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Drug Resistant Epilepsy
• Epilepsy

Intervention

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
• Placebo
Placebo on Week 1, Week 2, Week 3 and Week 4
• 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).

Locations

Country	Name	City	State
Australia	Austin Hospital	Heidelberg	Victoria
Australia	Royal Brisbane and Women's Hospital	Herston	Queensland
Australia	Alfred Health	Melbourne	Victoria
Australia	Royal Melbourne Hospital	Parkville	Victoria

Sponsors (1)

Lead Sponsor	Collaborator
ES Therapeutics Australia Pty Ltd

Country where clinical trial is conducted

Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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