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Trial registered on ANZCTR


Registration number
ACTRN12621000033842
Ethics application status
Approved
Date submitted
30/10/2020
Date registered
15/01/2021
Date last updated
14/02/2022
Date data sharing statement initially provided
15/01/2021
Type of registration
Prospectively registered

Titles & IDs
Public 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.
Scientific 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.
Secondary ID [1] 302661 0
none
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Epilepsy 319568 0
Condition category
Condition code
Neurological 317516 317516 0 0
Epilepsy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
ES-481 will be administered as 25 mg oral gelatin capsules.

The starting dose, dose administration schedule and the number of capsules of study medication (ES-481 or Placebo) to be administered per week in each 28-day treatment periods (Periods 1 and 2) are shown on the table below.

Week 1: 25 mg daily: 1 x 25 mg gelatin capsule Days 1 to 7 in Treatment
Period 1 and Days 43 to 49 in Treatment Period 2

Week 2: 25 mg twice a day: 2 x 25 mg gelatin capsules Days 8 to 14 in Treatment Period 1 and Days 50 to 56 in Treatment Period 2

Week 3: 50 mg twice a day: 4 x 25 mg gelatin capsules Days 15 to 21 in Treatment Period 1 and Days 57 to 63 in Treatment Period 2

Week 4: 75 mg twice a day: 6 x 25 mg gelatin capsules Days 22 to 28 in Treatment Period 1 and Days 64 to 70 in Treatment Period 2

In the 14-day step-down and washout period (following the two Treatment Periods), subjects will be washout of the medication as follows:

Day 1: 125 mg: 3 x 25 mg capsules in the morning and 2 x 25 mg capsules in the evening.
Day 2: 100 mg: 2 x 25 mg capsules in the morning and 2 x 25 mg capsules in the evening.
Day 3: 75 mg: 2 x 25 mg capsules in the morning and 1 x 25 mg capsules in the evening.
Day 4: 50 mg: 1 x 25 mg capsules in the morning and 1 x 25 mg capsules in the evening.
Day 5:50 mg: 1 x 25 mg capsules in the morning and 1 x 25 mg capsules in the evening.
Day 6: 25 mg: 1 x 25 mg gelatin capsule in the morning.
Day 7: 25 mg: 1 x 25 mg gelatin capsule in the morning.
Days 8 – 14: 0 mg: 7-day washout period.

Drug accountability will be performed on a weekly basis.

A 36-week open-label extension for subjects who successfully completed both treatment periods and in the opinion of the Principal Investigator demonstrated efficacy to study drug will be treated with maximum dose of 75 mg bid of ES-481
Intervention code [1] 318947 0
Treatment: Drugs
Comparator / control treatment
Placebo Control capsule containing microcellulose
Control group
Placebo

Outcomes
Primary outcome [1] 325553 0
A change in seizure frequency and activity assessed using a patient diary and continuous 24-hour EEG monitoring (composite outcome)
Timepoint [1] 325553 0
• Seizure Frequency: will be assessed daily by the patient using patient diary.
• Seizure Activity will be assessed by Continuous 24-Hour EEG Monitoring during the screening period and on days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70.
Secondary outcome [1] 388371 0
• To assess for changes in the Hamilton Anxiety Rating Scales (HAM-A)..
Timepoint [1] 388371 0
This outcome will be measured at screening and on study Days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70.
Secondary outcome [2] 389356 0
To assess for changes in the Hamilton Depression Rating Scale (HDRS).
Timepoint [2] 389356 0
This outcome will be measured at screening and on study Days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70.
Secondary outcome [3] 390244 0
Adverse Events -We will monitor clinically for adverse events for both CNS and Cardiovascular events.

For CNS adverse events we will monitor clinically by both physician observation and patient self-reporting for mood change, headache, agitation and anxiety.

For Cardiovascular Adverse events we will monitor changes in blood pressure and heart rate using physician clinical assessment, patient self-reporting along with regular assessment for changes in vital signs as well as periodic ECG for cardiac changes.
Timepoint [3] 390244 0
Adverse Events will be assessed and measured at screening and on study Days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70.
Secondary outcome [4] 390245 0
To Assess changes in hematology and chemistry laboratories by blood and serum assays and analysis.
Timepoint [4] 390245 0
This outcome will be measured at screening and on study Days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70.
Secondary outcome [5] 390246 0
Pharmacokinetic studies - The plasma concentration-time data will be analyzed using noncompartmental methods to determine the following PK parameters: Cmax, Tmax, AUC0-t, AUC0-inf, T½, CL/F and Vz/F. Additional PK parameters may be calculated as data permit.
Timepoint [5] 390246 0
Plasma samples will be drawn at screening and on study Days 1, 8, 15, 22, 28, 43, 50, 57, 64 and 70 to estimate pharmacokinetic parameters.

Eligibility
Key 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 anti-epileptic 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 approximately one (1) per hour on EEG recording.

For continued enrollment into Treatment Period 1, this will be confirmed by continuous 24-hour EEG performed during the 28-day screening period.

9. The subject is willing and able to comply with the study requirements
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Unwilling or inability to follow the procedures specified by the protocol
2. Pregnant 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:
o Hormonal contraception (birth control pills, injected hormones or vaginal ring)
o Intrauterine device
o Barrier methods (condom or diaphragm) combined with spermicide
o Surgical sterilization (hysterectomy, tubal ligation, or vasectomy)
4. Current treatment for another significant medical disorder, such as diabetes, 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 last month) of illicit drug use or alcohol dependence, and a commitment not to take 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 design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Active drug and placebo are identical in terms of shape, size, color, and weight. Both the Principal Investigator and dispensing pharmacist will be blinded. Each bottle will have a unique bottle number that can be traced back to the randomization and each unique bottle number will be assigned by the central dispensing Drug Depot.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Biostatistician to generate randomization sequence.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
The Intent-to-Treat population will include all subjects randomized and will be used to assess efficacy.

Mean difference in seizure frequency comparing ES-481 to Placebo and to baseline using repeated measures ANOVA.

Differences in interictal epileptiform discharges and electrographic seizures on the continuous 24-hour EEG using repeated measures ANOVA.

Mean difference in HAM-A and HDRS Hamilton Depression comparing ES-481 to Placebo and to baseline using repeated measure ANOVA.

The Safety population will include all subjects administered at least one dose of study medication (ES-481 or Placebo).

All safety and tolerability data will be summarized using descriptive statistics by study medication (ES-481 or Placebo). They will be listed and summarized in tabular and/or graphical form. No formal statistical testing will be performed on these data.

Pharmacokinetics: Plasma concentration of ES-481 will be summarized descriptively by dose in tabular and graphical formats. PK parameter estimates for ES-481 will be calculated using standard non-compartmental methods of analysis. PK parameters will be summarized descriptively be dose. Dose proportionality will be also assessed.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
18/01/2021
Actual
29/01/2021
Date of last participant enrolment
Anticipated
31/03/2022
Actual
Date of last data collection
Anticipated
31/10/2022
Actual
Sample size
Target
24
Accrual to date
2
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 17917 0
The Alfred - Melbourne
Recruitment hospital [2] 17918 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [3] 17919 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [4] 21715 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 31780 0
3004 - Melbourne
Recruitment postcode(s) [2] 31781 0
3050 - Parkville
Recruitment postcode(s) [3] 31782 0
3084 - Heidelberg
Recruitment postcode(s) [4] 36765 0
4029 - Herston

Funding & Sponsors
Funding source category [1] 307101 0
Commercial sector/Industry
Name [1] 307101 0
ES Therapeutics Australia Pty Ltd
Country [1] 307101 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
ES Therapeutics Australia Pty Ltd
Address
Level 17, 40 City Road
Southbank, VIC 3006
Country
Australia
Secondary sponsor category [1] 307962 0
None
Name [1] 307962 0
Address [1] 307962 0
Country [1] 307962 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307215 0
The Alfred Hospital Ethics Committee
Ethics committee address [1] 307215 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 307215 0
Australia
Date submitted for ethics approval [1] 307215 0
04/11/2020
Approval date [1] 307215 0
27/11/2020
Ethics approval number [1] 307215 0

Summary
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
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106434 0
Prof Dr. Terence J. O’Brien
Address 106434 0
The Alfred Centre
Level 6, 99 Commercial Rd
Melbourne Victoria 3004,

Country 106434 0
Australia
Phone 106434 0
+61390762029
Fax 106434 0
Email 106434 0
[email protected]
Contact person for public queries
Name 106435 0
Dr Keith Maher
Address 106435 0
ES Therapeutics Australia Pty Ltd
c/o Prime Accounting & Business Advisory Pty Ltd
Level 17, 40 City Road
Southbank, VIC, 3006 Australia
Country 106435 0
Australia
Phone 106435 0
+61 3 9013 4220
Fax 106435 0
Email 106435 0
[email protected]
Contact person for scientific queries
Name 106436 0
Dr Robert Niecestro.
Address 106436 0
ES Therapeutics Australia Pty Ltd
c/o Prime Accounting & Business Advisory Pty Ltd
Level 17, 40 City Road
Southbank, VIC, 3006 Australia
Country 106436 0
Australia
Phone 106436 0
+61 3 9013 4220
Fax 106436 0
Email 106436 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
As this is a Phase 2a study, only aggregate data may be published.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.