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

Primary Purpose

Drug Resistant Epilepsy

Status
Recruiting
Phase
Phase 2
Locations
Australia
Study Type
Interventional
Intervention
ES-481
Placebo
Open-Label Extension Study
Sponsored by
ES Therapeutics Australia Pty Ltd
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Drug Resistant Epilepsy

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Royal Brisbane and Women's HospitalRecruiting
  • Austin HospitalRecruiting
  • Alfred HealthRecruiting
  • Royal Melbourne HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Other

Arm Label

ES-481

Placebo

Open-Label Extension Study

Arm Description

Outcomes

Primary Outcome Measures

Seizure Frequency
A change in seizure frequency and activity assessed using a patient diary and continuous 24-hour EEG monitoring (composite outcome)

Secondary Outcome Measures

Hamilton Anxiety Rating Scale (HAM-A)
To assess for changes in the HAM-A
Hamilton Depression Rating Scale (HDRS)
To assess for changes in HDRS
Adverse Events
Monitoring clinically for adverse events for both CNS and Cardiovascular events
Laboratory Assessments - Hematology
Assess changes in hematology and chemistry laboratories by blood and serum assays and analysis
Laboratory Assessments - Chemistry
Assess changes in hematology and chemistry laboratories by blood and serum assays and analysis
Pharmacokinetics (PK) - Cmax
Plasma concentration-time data will be analyzed using non compartmental methods to determine the following PK parameter: Cmax
Pharmacokinetics (PK) - Tmax
Plasma concentration-time data will be analyzed using non compartmental methods to determine the following PK parameter: Tmax
Pharmacokinetics (PK) - AUC0-t
Plasma concentration-time data will be analyzed using non compartmental methods to determine the following PK parameter: AUC0-t
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
Pharmacokinetics (PK) - CL/F
Plasma concentration-time data will be analyzed using non compartmental methods to determine the following PK parameter: CL/F
Pharmacokinetics (PK) - Vz/F
Plasma concentration-time data will be analyzed using non compartmental methods to determine the following PK parameter: Vz/F

Full Information

First Posted
January 13, 2021
Last Updated
March 1, 2023
Sponsor
ES Therapeutics Australia Pty Ltd
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1. Study Identification

Unique Protocol Identification Number
NCT04714996
Brief Title
Efficacy, Safety and Pharmacokinetics of ES-481 in Adult Patients With Drug Resistant Epilepsy
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 30, 2020 (Actual)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
ES Therapeutics Australia Pty Ltd

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief 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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Drug Resistant Epilepsy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Double-blind, placebo-controlled
Allocation
Randomized
Enrollment
24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
ES-481
Arm Type
Experimental
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Title
Open-Label Extension Study
Arm Type
Other
Intervention Type
Drug
Intervention Name(s)
ES-481
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo on Week 1, Week 2, Week 3 and Week 4
Intervention Type
Drug
Intervention Name(s)
Open-Label Extension Study
Intervention Description
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).
Primary Outcome Measure Information:
Title
Seizure Frequency
Description
A change in seizure frequency and activity assessed using a patient diary and continuous 24-hour EEG monitoring (composite outcome)
Time Frame
Continuous and at Days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70
Secondary Outcome Measure Information:
Title
Hamilton Anxiety Rating Scale (HAM-A)
Description
To assess for changes in the HAM-A
Time Frame
Collected at screening, Days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70
Title
Hamilton Depression Rating Scale (HDRS)
Description
To assess for changes in HDRS
Time Frame
Collected at screening, Days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70
Title
Adverse Events
Description
Monitoring clinically for adverse events for both CNS and Cardiovascular events
Time Frame
Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70
Title
Laboratory Assessments - Hematology
Description
Assess changes in hematology and chemistry laboratories by blood and serum assays and analysis
Time Frame
Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70
Title
Laboratory Assessments - Chemistry
Description
Assess changes in hematology and chemistry laboratories by blood and serum assays and analysis
Time Frame
Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70
Title
Pharmacokinetics (PK) - Cmax
Description
Plasma concentration-time data will be analyzed using non compartmental methods to determine the following PK parameter: Cmax
Time Frame
Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70
Title
Pharmacokinetics (PK) - Tmax
Description
Plasma concentration-time data will be analyzed using non compartmental methods to determine the following PK parameter: Tmax
Time Frame
Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70
Title
Pharmacokinetics (PK) - AUC0-t
Description
Plasma concentration-time data will be analyzed using non compartmental methods to determine the following PK parameter: AUC0-t
Time Frame
Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70
Title
Pharmacokinetics (PK) - AUC0-inf. T1/2
Description
Plasma concentration-time data will be analyzed using non compartmental methods to determine the following PK parameter: AUC0-inf. T1/2
Time Frame
Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70
Title
Pharmacokinetics (PK) - CL/F
Description
Plasma concentration-time data will be analyzed using non compartmental methods to determine the following PK parameter: CL/F
Time Frame
Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70
Title
Pharmacokinetics (PK) - Vz/F
Description
Plasma concentration-time data will be analyzed using non compartmental methods to determine the following PK parameter: Vz/F
Time Frame
Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Robert Niecestro, PhD
Phone
917-733-5311
Email
rniecestro@estherapeutics.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Terence O'Brien
Organizational Affiliation
The Alfred
Official's Role
Principal Investigator
Facility Information:
Facility Name
Royal Brisbane and Women's Hospital
City
Herston
State/Province
Queensland
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
David Reutens
Facility Name
Austin Hospital
City
Heidelberg
State/Province
Victoria
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Saul Mullen
Facility Name
Alfred Health
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3004
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Terence O'Brien
Facility Name
Royal Melbourne Hospital
City
Parkville
State/Province
Victoria
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
John Paul Nicolo

12. IPD Sharing Statement

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

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