Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619001591145p
Ethics application status
Submitted, not yet approved
Date submitted
8/11/2019
Date registered
19/11/2019
Date last updated
19/11/2019
Date data sharing statement initially provided
19/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1 study to evaluate safety and tolerability of ES-481 in healthy volunteers
Scientific title
A Phase 1, Open-Label, Single Ascending Dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of ES-481 after Oral Administration in Healthy Volunteers
Secondary ID [1] 299741 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Epilepsy 315093 0
Condition category
Condition code
Neurological 313427 313427 0 0
Epilepsy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Oral gelatin capsule of ES-481 will be administered in total 10 Cohorts as below.
Cohort 1: total dose 3 mg; 1 capsule of 3 mg ES-481
Cohort 2: total dose 6 mg; 2 capsule of 3 mg ES-481
Cohort 3: total dose 12 mg; 4 capsule of 3 mg ES-481
Cohort 4: total dose 25 mg; 1 capsule of 25 mg ES-481
Cohort 5: total dose 37 mg; 1 capsule of 25 mg ES-481 + 4 capsules of 3 mg ES-481
Cohort 6: total dose 50 mg; 2 capsule of 25 mg ES-481
Cohort 7: total dose 62 mg; 2 capsule of 25 mg ES-481 + 4 capsules of 3 mg ES-481
Cohort 8: total dose 75 mg; 3 capsule of 25 mg ES-481
Cohort 9: total dose 87 mg; 3 capsule of 25 mg ES-481 + 4 capsules of 3 mg ES-481
Cohort 10: total dose 100 mg; 4 capsule of 25 mg ES-481

Cohorts will be mutually exclusive.
Intervention code [1] 316004 0
Treatment: Drugs
Comparator / control treatment
Matching placebo oral gelatin capsules with methylcellulose administered per Cohort will be identical to the above cohort dose of investigational product
Control group
Placebo

Outcomes
Primary outcome [1] 321905 0
To evaluate the pharmacokinetics of Oral ES-481
Timepoint [1] 321905 0
Blood for PK analysis will be collected at 8 AM (time 0 hours, prior to the oral dose of study drug /placebo and after an overnight fast, at 0.25, 0.5, 1, 2, 4, 8, 12, 16, and 24 hours following the oral administration of study drug/placebo on Day 1 and at 36 and 48 (Day 2) hours after the oral administration of study drug/placebo on Day 2.

Below PK parameters will be assessed derived from plasma data.

Peak concentration in plasma (Cmax);
Time to peak concentration in plasma (Tmax);
Area under the plasma concentration-time curve (AUC) from time zero to last quantifiable concentration (AUClast);
AUC from time zero to infinity (AUCinf);
Apparent total body clearance from plasma (CL)
Apparent renal clearance from plasma (CLr);
Elimination half-life (t½);
Secondary outcome [1] 376637 0
To evaluate the safety and tolerability of Oral ES-481 after a single dose
Timepoint [1] 376637 0
Adverse events will be monitored throughout the study from the date of informed consent signed.

Vital signs will be measured at screening, before administration of ES-481; on Day 1 and at 0.5, 1, 2, 4, 12, 24 (Day 1), 48 (Day 2), 72 (Day 3), and 96 (Day 4) hours after the oral administration of study drug or placebo and at the follow-up visit.

Hematology, Chemistry and Urinalysis will be taken at screening, Day -1, and 24 (Day 1), 48 (Day 2), 72 (Day 3) and 96 (Day 4) hours after the oral administration of study drug/placebo and at the follow-up visit

Physical examination will be performed at screening, Day-1, and 24 (Day 1), 48 (Day 2), 72 (Day 3) and 96 (Day 4) hours after the oral administration of study drug/placebo and at the follow-up visit.

Neurological assessment/examination will be performed at screening, Day -1, after check-in, and on Day 1 approximately 3, 6, and 24 hours after the administration of study drug/placebo.

12-lead ECG will be collected at pre-dose on Day 1 and post dose at 0.5, 1, 2, 4, 6, 9, 12, and 24 hours on Day 1, 48 (Day 2), 72 (Day 3) and 96 (Day 4) hours and at the follow-up visit.

Columbia-Suicide Severity Rating Scale will be done at screening and on Days -1, 1, 2, 3, and 4 and at the follow-up visit.

Eligibility
Key inclusion criteria
1. Written informed consent obtained
2. The subject is a healthy male or non-childbearing or breast-feeding female or male, 18 to 55 years of age, inclusive
3. Body weight 45 to 85 kg, and body mass index (BMI) 18 to 29.9 kg/m2, inclusive.
4. If female, is of non-childbearing potential with documentation provided by healthcare professional or post-menopausal [defined as at least 2 years at Screening without menses and with follicle stimulating hormone
5. If male, the subject agrees to sexual abstinence, or is surgically sterile or is using a medically acceptable method to prevent pregnancy and agrees to continue using this method from screening until 30 days after the last dose administration
6. The subject must have screening and Day -1 clinical laboratory test results within normal limits or, if abnormal, the results are not clinically significant as determined by the Principal Investigator
7. Healthy as determined by the Principal Investigator based on Medical History, Physical Examination, Normal Electrocardiograms (ECG) and Normal Electroencephalogram (EEG) recordings done during the screening visit
8. Creatinine clearance (CrCL) > 60 mL/min as estimated by the Cockcroft-Gault equation.
9. The subject is willing and able to comply with the study requirements
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Unwillingness or inability to follow the procedures specified by the protocol.
2. History or family history of seizures.
3. Major surgery within 3 months or minor surgery within 1 month prior to screening
4. The subject has a positive serology test for human immunodeficiency virus, antibody, hepatitis C virus (HCV) antibody or hepatitis B surface antigen (HbsAg) at screening
5. The subject has a history of severe allergic or anaphylactic reactions
6. The subject has received a vaccine within 60 days prior to study drug administration
7. The subject has a history of any clinically significant cardiovascular, gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other major disease or malignancy, excluding non-melanoma skin cancer
8. Potential for suicidal ideation as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) during the screening visit
9. The subject has any clinically significant abnormality of the physical examination, ECG, EEG and protocol-defined clinical laboratory tests
10. Heart rate less than 40 or greater than 90 bpm; systolic blood pressure greater than 140 mm Hg; diastolic blood pressure greater than 90 mm Hg
11. A QTc(B) interval of greater than 430 msec (for males) and greater than 450 msec (for females) at Screening or Day -1
12. A history of unexplained syncope, cardiac arrest, unexplained cardiac arrhythmias or torsades de pointes, structural heart disease, or a family history of Long QT Syndrome (LQTS)
13. Participated in any interventional clinical study or has been treated with any investigational drugs within 30 days or 5 half-lives prior to the initiation of screening
14. The subject is suicidal or has a history of suicide attempt within the past 6 months as determined using the C-SSRS at screening.
15. The subject has/had a symptomatic, viral, bacterial or fungal infection within 1 month prior to study drug administration
16. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements, and hormone replacement therapy within 7 days or 5 half-lives,
17. Regular use of tobacco or nicotine-containing products within 4 weeks prior to screening or urinary continine level indicative of active smoking at screening and/or at Day -1
18. Regular alcohol consumption,
19. History of drug abuse within the previous 2 years
20. The subject has a positive urine screen for drugs of abuse
21. History of CYP3A4 inducer use in the 1 month prior to Day -1 and continuing throughout the study
22. The subject has donated or lost greater than or equal to 450 mL of blood or received a transfusion of any blood or blood products within 90 days prior to screening, or has donated plasma within 7 days prior to Day -1
23. The subject has any other condition, which in the opinion of the Principal Investigator, precludes the subject’s participation in the study
24. Subjects unwilling to abstain from consuming grapefruit, grapefruit juice, or Seville oranges

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)
Participants will be randomly assigned to once-daily dosing of ES-481 or placebo based on the randomization scheme. The pharmacist will dispense the study drug for individual subject dosing according to the randomization code.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
The subjects will be randomized into cohorts, the cohorts will start sequentially in escalating order, with each subject within a cohort randomized to either the active drug or placebo
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
20/12/2019
Actual
Date of last participant enrolment
Anticipated
1/06/2020
Actual
Date of last data collection
Anticipated
9/06/2020
Actual
Sample size
Target
80
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 15120 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 28414 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 304215 0
Commercial sector/Industry
Name [1] 304215 0
ES Therapeutics LLC
Country [1] 304215 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
ES Therapeutics LLC
Address
510 Madison Avenue, 7th Floor
New York, NY 10022
Country
United States of America
Secondary sponsor category [1] 304448 0
None
Name [1] 304448 0
Address [1] 304448 0
Country [1] 304448 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 304677 0
The Alfred Hospital Ethics Committee
Ethics committee address [1] 304677 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 304677 0
Australia
Date submitted for ethics approval [1] 304677 0
11/11/2019
Approval date [1] 304677 0
Ethics approval number [1] 304677 0

Summary
Brief summary
This is a first-in-human, Phase 1 single center, open-label, randomized single ascending dose study of ES-481 to evaluate the PK, safety and tolerability of ES-481 in healthy subjects on a fixed dose.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 97826 0
Dr Jason Lickliter
Address 97826 0
Nucleus Network
Level 5, Burnet Tower, AMREP Precinct,
89 Commercial Road Melbourne,
VIC 3004
Country 97826 0
Australia
Phone 97826 0
+61 390768960
Fax 97826 0
Email 97826 0
[email protected]
Contact person for public queries
Name 97827 0
Dr Robert Niecestro
Address 97827 0
ES Therapeutics LLC
c/o Armistice Capital LLC
510 Madison Avenue, 7th Floor
New York, NY 10022
Country 97827 0
United States of America
Phone 97827 0
+1 212 231 4942
Fax 97827 0
Email 97827 0
[email protected]
Contact person for scientific queries
Name 97828 0
Dr Keith Maher
Address 97828 0
ES Therapeutics LLC
c/o Armistice Capital LLC
510 Madison Avenue, 7th Floor
New York, NY 10022
Country 97828 0
United States of America
Phone 97828 0
+1 212 231 4942
Fax 97828 0
Email 97828 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 1 study, only aggregate data may be posted/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.