Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000562572
Ethics application status
Approved
Date submitted
12/03/2024
Date registered
3/05/2024
Date last updated
25/06/2024
Date data sharing statement initially provided
3/05/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase 1 Study to Investigate SIR2501 in Healthy Adult Participants
Scientific title
A Randomized, Double-Blind, and Placebo-Controlled Phase 1 Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics with Single and Multiple Oral Doses of SIR2501 in Healthy Adult Participants
Secondary ID [1] 311675 0
Sironax Australia Study SIR2501-AU-101
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neuropathies 333136 0
Neurodegenerative disorders 333503 0
Condition category
Condition code
Neurological 329832 329832 0 0
Neurodegenerative diseases
Neurological 330179 330179 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
SIR2501-AU-101 is a two-part study containing parts 1 and 2 with Part 2 also containing three parts -Part 2A, 2B and 2C. Each study part and stage will involve unique participants.
Part 1: Single ascending dose cohorts
Part 1 evaluates the single-dose administration of SIR2501 or matched placebo (a tablet that looks the same as the study drug but has no active substances): 10mg, 30mg, 100mg, 300mg, 600mg and 1000mg respectively in cohorts 1-6. Each cohort will consist of 8 participants who will each receive a single dose of investigational drug or matched placebo under fasted state (after an overnight fast of at least 10 hours prior to dosing), Healthy volunteers will stay in the clinical research unit for the entire duration of dosing and will take study drug under direct supervision of the clinical research unit staff.
Part 1 cohort 3 - Participants in Cohort 3 who complete the assigned SAD dosing will continue to remain in the clinical research unit to receive an additional assigned study intervention. The second dosing will occur after a washout period of 7 days from their first dose and upon consumption of a high-fat breakfast participants will receive the same assigned study intervention as a part of the Food Effect study. Healthy volunteers will stay in the clinical research unit for the entire duration of dosing and will take study drug under direct supervision of the clinical research unit staff.
Each of the SAD cohorts will be observed for 10 days after the Day 1 dosing. Safety, tolerability, and available PK data will be reviewed by the SRC for dose escalation and the actual doses to be administered may be adjusted accordingly.
Part 2: Multiple dose cohorts
Part 2 of the study consists of three parts.
Part 2A: Multiple ascending dose cohorts
Each cohort will consist of 10 participants who will each receive SIR2501 or matched placebo (a tablet that looks the same as the study drug but has no active substances): 30mg, 100mg,200mg and 400mg respectively in cohorts 1-4 given by oral administration twice daily for 10 days. Healthy volunteers will stay in the clinical research unit for the entire duration of dosing and will take study drug under direct supervision of the clinical research unit staff.
In Part 2A, after an observation and follow-up period of 20 days from the first day of dosing) and review of the safety, tolerability, and available PK data of all participants enrolled in the previous cohorts, the next actual dose cohort may be adjusted by the SRC. These dose adjustments may involve either an increase or a decrease in the planned dose or a change in the dosing frequency however the maximum dose will not exceed 400mg BID and the maximum frequency of dosing will not exceed twice daily dosing.
Part 2B: Drug-Drug Interaction Study
Ten (10) healthy male and female adult volunteers will be enrolled to Part 2B of the study which aims to characterize the drug-drug interaction (DDI) potential of SIR2501 as a perpetrator of midazolam.
For all participants:
• Part 2B will be an open label design where each participant will receive SIR2502 and midazolam,
. On Day 1,5 and 12 participants will each receive a single oral dose of midazolam 2 mg.
• On Days 3 through 12, participants will each receive SIR2501 100mg given by oral administration twice daily.
Healthy volunteers will stay in the clinical research unit for the entire duration of dosing and will take study drug under direct supervision of the clinical research unit staff.
The actual SIR2501 dose including dose regimen for Part 2B and conditions for the administration of the study intervention will be determined by SRC after reviewing of the safety, tolerability, and available PK data of Part 1 and Part 2A. In Part 2B, after a dosing period of 12 days, participants will be observed and followed for safety for a further 10 days.
Part 2C: China Cohort
Part 2C of the study will be conducted in China. One cohort of 14 participants will each receive SIR2501 or matched placebo (a tablet that looks the same as the study drug but has no active substances): 200mg given by oral administration twice daily for 10 days. Healthy volunteers will stay in the clinical research unit for the entire duration of dosing and will take study drug under direct supervision of the clinical research unit staff. After an observation and follow-up period of 20 days from the first day of dosing) participants will return to the clinical research unit for an End of Study Visit. Completion of this follow up visit by the last participant in Part 2C will mark the end of the active study.
Part 2C will commence after the same dose level is reviewed by the SRC in Part 2A. however the planned 200mg dose for Part 2C maybe adjusted based on the outcome of SRC review of Part 2A.

In all study parts adherence to the intervention will be done via supervised drug administration.
Intervention code [1] 328140 0
Treatment: Drugs
Comparator / control treatment
Matching placebo: The placebo tablets contain white to off-white powder, consisting of the excipient’s microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal silica dioxide and magnesium stearate. The tablets have the exact same composition as the active drug product minus the active ingredient.
Control group
Placebo

Outcomes
Primary outcome [1] 337599 0
Integrated safety evaluation assessed as a composite primary outcome
Timepoint [1] 337599 0
Part 1: Single Ascending Dose (except Cohort 3): Day -1 (the day before dosing) to Day 11 (10 days post-dose) clinical laboratory blood tests and urinalysis will be assessed at Screening and on Day -1, Day 2 (1 day post dose), Day 3 (2 days post dose), Day 5 (4 days post dose), and Day 11 (10 days post dose).
A complete physical examination will be assessed at screening, Day -1, and Day 5.
Vital signs will be assessed at Screening and on Day -1, Day 1, Day 2, Day 3, Day 4, Day 5, and Day 11
12-Lead ECG will be assessed at Screening and on Day 1, Day 2, Day 3, Day 4, Day 5, and Day 11
AEs/SAEs will be assessed at all timepoints.
Part 1: Food Effect Cohort (Cohort 3): Day -1 (the day before dosing) to Day 18 (17 days post-the first dose) clinical laboratory blood tests and urinalysis will be assessed at Screening and on Day -1, Day 2 (1 day post the first dose), Day 3 (2 day post the first dose), Day 5 (4 day post the first dose), Day 9 (Day after second dose), Day 10 (2 days post second dose), Day 12 (4 days post second dose), and Day 18 (10 days post second dose),.
A complete physical examination will be assessed at screening, Day -1, and Day 12.
Vital signs will be assessed at Screening and on Day -1, Day 1, Day 2, Day 3, Day 4, Day 5, Day 7, Day 8, Day 9, Day 10, Day 11, Day 12 and Day 18
12-Lead ECG will be assessed at Screening and on Day 1, Day 2, Day 3, Day 4, Day 5, Day 8, Day 9, Day 10, Day 11, Day 12 and Day 18
AEs/SAEs will be assessed at all timepoints.

Part 2A: Multiple Ascending Dose: Day -1 (the day before dosing) to Day 20 (10 days post last dose) clinical laboratory blood tests and urinalysis will be assessed at Screening and on Day -1, Day 3 (2 day post the first dose), Day 5 (4 day post the first dose), Day 7 (the 7th day of dosing), Day 9 (the 9th day of dosing), Day 11 (1 day post last dose), Day 14 (4 days post last dose), and Day 20 (10 days post last dose).
A complete physical examination will be assessed at Screening and Day 14.
Vital signs will be assessed at Screening and on Day -1, Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 11, Day 12, Day 13, Day 14, and Day 20
12-Lead ECG will be assessed Screening and on Day 1, Day 3, Day 5, Day 7, Day 9, Day 11, Day 14 and Day 20.
AEs/SAEs will be assessed at all timepoints.

Part 2B: Drug-Drug Interaction Cohort: Day -1 (the day before dosing) to Day 22 (10 days post last dose) clinical laboratory blood tests and urinalysis will be assessed at Screening and on Day -1, Day 1, Day 2 ( 1 day post the first midazolam dosing), Day 4 ( 1 day post the first 2501 dosing), Day 7 (2 days post the second midazolam dosing), Day 10 (7 days post the first 2501 dosing) , Day 14 (2 days post last 2501 dosing) and Day 22 (10 days post last 2501 dosing).
A complete physical examination will be assessed at Screening and Day 14.
Vital signs will be assessed at Screening and on Day -1, Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 11, Day 12, Day 13, Day 14, and Day 22
12-Lead ECG will be assessed Screening and on Day 1, Day 3, Day 5, Day 7, Day 9, Day 12, Day 14 and Day 22.
AEs/SAEs will be assessed at all timepoints.
Secondary outcome [1] 432469 0
Pharmacokinetic profile Part 1 (SAD)
Timepoint [1] 432469 0
Blood samples collected at: pre-dose and at and at 0.25, 0.5, 1, 2, 3, 4, 6, 8,10, 12, 24,48, 72 and 96-hours post-dose.
Secondary outcome [2] 432470 0
Pharmacokinetic profile Part 2A (MAD)
Timepoint [2] 432470 0
blood samples collected on Day 1 pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post the D1 morning dose. On Days 2 through 9 plasma samples will be collected prior to and 2 hours after the morning dose and commencing on Day 10 blood samples will be collected pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 36, 48, 60, 72 and 96 hours after the D10 morning dose. A CSF sample will be collected within Days 6 – 9 between 2 to 6 hours post-dose for Cohort 2
Secondary outcome [3] 434446 0
Pharmacokinetic profile Part 2B (DDI)
Timepoint [3] 434446 0
Midazolam - blood samples collected on Day 1, Day 5 and 12 pre-dose and at 0.25,0.5,1,1.5,2,3,4,6,8, 10,12,16 and 24 hours post the Day 1 midazolam dose.
SIR2501 - blood samples collected on Days 3 through 12 prior to and 2 hours after the morning dose.
Secondary outcome [4] 434447 0
Pharmacokinetic profile Part 2C (MAD)
Timepoint [4] 434447 0
blood samples collected on Day 1 pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post the D1 morning dose. On Days 2 through 9 plasma samples will be collected prior to and 2 hours after the morning dose and commencing on Day 10 blood samples will be collected pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12,36, 48, 60, 72 and 96 hours after the D10 morning dose
Secondary outcome [5] 434449 0
Pharmacodynamic profile Part 1 (SAD)
Timepoint [5] 434449 0
Blood samples collected on Day 1 pre-dose and 2,24 and 72 hours post the D1 dose
Secondary outcome [6] 434450 0
Pharmacodynamic profile Part 2A (MAD)
Timepoint [6] 434450 0
Blood samples collected on Days 1 and 7 pre-dose and 2 hours after the morning dose. On Day 10 blood samples will be collected 2, 24 and 72 hours after morning dose.
Secondary outcome [7] 434451 0
Pharmacodynamic profile Part 2C (MAD)
Timepoint [7] 434451 0
Blood samples collected on Days 1 and 7 pre-dose and 2 hours after the morning dose. On Day 10 blood samples will be collected 2, 24 and 72 hours after morning dose

Eligibility
Key inclusion criteria
• Must be capable of giving a signed informed consent
• Participants in good health based on medical history, physical examinations, vital
signs, 12-lead ECGs, clinical laboratory tests as determined by the Investigator.
• Body mass index (BMI) within the range of 18~32 kg/m2 (inclusive) with a minimum
body weight of 50 kg at the screening visit.
• Adhere to effective double barrier contraception or are proven post-menopausal
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
• Any clinically significant abnormalities in laboratory test results deemed clinically significant by the Investigator.
• History of non-febrile seizures
• History of a suicide attempt in the past 12 months or being seen by the Investigator as having significant risk of suicide
• Positive pregnancy test at Screening or Day-1
• Active or prior hepatitis B infection or positive test for HIV or Hepatitis C
• History of lactose intolerance
• 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 that is not well managed and stable.as determined by the Investigator.
• Hospital admission or major surgery within 60 days prior to Screening

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomization using a randomization table created by computer software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Other
Other design features
Part 1: Single ascending dose cohorts, two arm randomised design
Part 2: Multiple dose cohorts, consists of three parts.
Part 2A: Multiple ascending dose cohorts, two arm randomised design
Part 2B: open label design where each participant will receive SIR2502 and midazolam in a non-randomised allocation.
Part 2C: Single China Cohort, two arm randomised design
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
Listings and tabulations of safety and tolerability variables
Pharmacokinetic analysis and modelling to estimate and visualise standard parameters
Sample size is based on customary practice in Phase 1 clinical studies

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
29/05/2024
Actual
29/05/2024
Date of last participant enrolment
Anticipated
3/01/2025
Actual
Date of last data collection
Anticipated
25/01/2025
Actual
Sample size
Target
112
Accrual to date
2
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 26238 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 42206 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 316004 0
Commercial sector/Industry
Name [1] 316004 0
Sironax Australia Pty Ltd
Country [1] 316004 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Sironax Australia Pty Ltd
Address
Country
Australia
Secondary sponsor category [1] 318153 0
None
Name [1] 318153 0
Address [1] 318153 0
Country [1] 318153 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314828 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 314828 0
Ethics committee country [1] 314828 0
Australia
Date submitted for ethics approval [1] 314828 0
18/03/2024
Approval date [1] 314828 0
08/05/2024
Ethics approval number [1] 314828 0
168/24

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 132854 0
Dr Phillip Ryan
Address 132854 0
Nucleus Network Pty Ltd Level 5, Burnet Tower, 89 Commercial Rd, Melbourne 3004, Victoria
Country 132854 0
Australia
Phone 132854 0
+61 3 90768960
Fax 132854 0
Email 132854 0
[email protected]
Contact person for public queries
Name 132855 0
Dr Phillip Ryan
Address 132855 0
Nucleus Network Pty Ltd Level 5, Burnet Tower, 89 Commercial Rd, Melbourne 3004, Victoria
Country 132855 0
Australia
Phone 132855 0
+61 1800 243 733
Fax 132855 0
Email 132855 0
[email protected]
Contact person for scientific queries
Name 132856 0
Dr Phillip Ryan
Address 132856 0
Nucleus Network Pty Ltd Level 5, Burnet Tower, 89 Commercial Rd, Melbourne 3004, Victoria
Country 132856 0
Australia
Phone 132856 0
+61 1800 243 733
Fax 132856 0
Email 132856 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
No individual data will be released in any form


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.