Drug Resistant EpilepsyPhase 2NCT04714996
Efficacy, Safety and Pharmacokinetics of ES-481 in Adult Patients With Drug Resistant Epilepsy
A Phase 2 study testing ES-481 and Open-Label Extension Study in people with Drug Resistant Epilepsy, run by ES Therapeutics Australia Pty Ltd at 4 sites in Australia.
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 Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Drug Resistant Epilepsy
- What is being tested?
- ES-481 and Open-Label Extension Study
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 24 participants
- Where
- 4 sitesAustralia
- Study dates
- 30 Oct 2020to Dec 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
4 sites in 1 country.
Australia4 sites, 4 recruiting
- Recruiting
Austin Hospital
Heidelberg, Victoria
Saul Mullen
- Recruiting
Royal Brisbane and Women's Hospital
Herston, Queensland
David Reutens
- Recruiting
Alfred Health
Melbourne, Victoria, 3004
Terence O'Brien
- Recruiting
Royal Melbourne Hospital
Parkville, Victoria
John Paul Nicolo
About this study
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
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
- Conditions
- Drug Resistant Epilepsy
- Being tested
- ES-481, Placebo, Open-Label Extension Study
- Medical subject headings
- Drug Resistant Epilepsy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ES-481Drug
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
PlaceboDrug
Placebo on Week 1, Week 2, Week 3 and Week 4
Open-Label Extension StudyDrug
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).
| Study group | Role | What they receive |
|---|---|---|
| ES-481 | Experimental | Not described Receives: Drug: ES-481 |
| Placebo | Placebo comparator | Not described Receives: Drug: Placebo |
| Open-Label Extension Study | Other | Not described Receives: Drug: Open-Label Extension Study |
What is being measured
The primary outcome is the main question the study is designed to answer.
Seizure Frequency
A change in seizure frequency and activity assessed using a patient diary and continuous 24-hour EEG monitoring (composite outcome)
Measured: Continuous and at Days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70
Secondary outcomes (11)
Hamilton Anxiety Rating Scale (HAM-A)
To assess for changes in the HAM-A
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jan 2021
- Study start30 Oct 2020
- Primary completionDec 2023 (estimated)
- Study completionDec 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Drug Resistant EpilepsyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 24 participants (estimated)
Sponsor and investigators
- Lead sponsor
- ES Therapeutics Australia Pty Ltd
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Terence O'Brien, Principal investigator, The Alfred
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04714996
- Sponsor's protocol ID
- ES-481-C201
- Status last verified
- Mar 2023
- First submitted
- 13 Jan 2021
- Last updated
- 2 Mar 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Foster EC, Millist L, Germaine J, Chamorro S, Roberts C, Nicolo JP, Hosking S, Perucca P, Mullen S, Robinson H, Wharrie R, Walsh B, Reutens D, Irwin K, Zeng H, Niecestro R, O'Brien TJ. A first in disease trial of the safety, tolerability, and anti-seizure effects of ES-481 in drug-resistant epilepsy. Epilepsia Open. 2026 Aug;11(4):1329-1342. doi: 10.1002/epi4.70294. Epub 2026 Jun 18.
PubMed 42312676
Study at a glance
From the registry record, last updated by the sponsor on 2 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04714996
- Acronym / sponsor ID
- ES-481-C201
- Conditions
- Drug Resistant Epilepsy
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 24 participants (estimated)
- Lead sponsor
- ES Therapeutics Australia Pty LtdIndustry (pharma, biotech, devices)
- Study start
- 30 Oct 2020 (actual)
- Primary completion
- Dec 2023 (estimated)
- Study completion
- Dec 2023 (estimated)
- First posted
- 20 Jan 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| ES-481 | Experimental | Drug: ES-481 |
| Placebo | Placebo comparator | Drug: Placebo |
| Open-Label Extension Study | Other | Drug: Open-Label Extension Study |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- 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
Key exclusion criteria (10 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ES-481Treatment 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 | Drug | ES-481 |
| PlaceboPlacebo on Week 1, Week 2, Week 3 and Week 4 | Drug | Placebo |
| Open-Label Extension StudyDosing 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). | Drug | Open-Label Extension Study |
Primary outcome
Seizure Frequency
Time frame: Continuous and at Days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70
A change in seizure frequency and activity assessed using a patient diary and continuous 24-hour EEG monitoring (composite outcome)
11 secondary outcomes
Hamilton Anxiety Rating Scale (HAM-A)
Time frame: Collected at screening, Days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70
Hamilton Depression Rating Scale (HDRS)
Time frame: Collected at screening, Days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70
Adverse Events
Time frame: Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70
Laboratory Assessments - Hematology
Time frame: Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70
Laboratory Assessments - Chemistry
Time frame: Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70
Pharmacokinetics (PK) - Cmax
Time frame: Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70
Pharmacokinetics (PK) - Tmax
Time frame: Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70
Pharmacokinetics (PK) - AUC0-t
Time frame: Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70
Pharmacokinetics (PK) - AUC0-inf. T1/2
Time frame: Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70
Pharmacokinetics (PK) - CL/F
Time frame: Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70
Pharmacokinetics (PK) - Vz/F
Time frame: Collected at screening, Days 1, 8, 15 22, 28, 43, 50, 57, 64 and 70
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Mar 2023.
- Derived from this study: PubMed 42312676Foster EC, Millist L, Germaine J, Chamorro S, Roberts C, Nicolo JP, Hosking S, Perucca P, Mullen S, Robinson H, Wharrie R, Walsh B, Reutens D, Irwin K, Zeng H, Niecestro R, O'Brien TJ. A first in disease trial of the safety, tolerability, and anti-seizure effects of ES-481 in drug-resistant epilepsy. Epilepsia Open. 2026 Aug;11(4):1329-1342. doi: 10.1002/epi4.70294. Epub 2026 Jun 18.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Terence O'Brien principal investigator
The Alfred
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing ES-481 and Open-Label Extension Study in people with Drug Resistant Epilepsy, run by ES Therapeutics Australia Pty Ltd at 4 sites in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 2 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Robert Niecestro, PhD (917-733-5311, rniecestro@estherapeutics.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Seizure Frequency (time frame: Continuous and at Days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04714996, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Mar 2023.