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Trial registered on ANZCTR


Registration number
ACTRN12623000790640
Ethics application status
Approved
Date submitted
11/07/2023
Date registered
20/07/2023
Date last updated
1/09/2024
Date data sharing statement initially provided
20/07/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A Randomised, Double-Blind and Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SIR9900 after Oral Administrations in Healthy Elderly Volunteers. (Multiple Ascending Dose (MAD), Part 2 Cohort 5).
Scientific title
A Randomised, Double-Blind and Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SIR9900 after Oral Administrations in Healthy Elderly Volunteers
Secondary ID [1] 309949 0
SIR9900-AU-101
Universal Trial Number (UTN)
Trial acronym
Linked study record
ACTRN12623000696695. This record documents an additional Cohort of ACTRN12623000696695 but in a different patient population.

Health condition
Health condition(s) or problem(s) studied:
Inflammatory diseases, particularly in central nervous system 330431 0
Degenerative diseases, particularly in central nervous system 330432 0
Condition category
Condition code
Inflammatory and Immune System 327274 327274 0 0
Other inflammatory or immune system disorders
Neurological 327275 327275 0 0
Neurodegenerative diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part 2: MAD. Approximately 10 healthy elderly volunteers in cohort 5 in Part 2, with 8 participants randomised to receive an oral dose of SIR9900 once daily (QD) for 10 consecutive days and 2 to receive an oral dose of placebo once daily for 10 consecutive days. The following dose level cohort is planned:

• Cohort 5# (healthy elderly volunteers): 30 mg

# The MAD cohort 5 (healthy elderly volunteers, 30 mg) can proceed after Safety Review Committee (SRC) review of MAD cohort 3 (healthy adults, 30 mg), and so may overlap with MAD cohort 4 (60 mg). MAD cohort 3 and cohort 4 are from the linked study ACTRN12623000696695.

During the treatment period of Part 2 MAD study, participants will remain admitted to the Clinical Research Unit (CRU) from Day 1 until Day 14.

SIR9900 will be supplied as tablets for oral administration at dosage strength of 10mg.

Adherence to Intervention will be managed via recording in appropriate drug accountability records.
Intervention code [1] 326368 0
Treatment: Drugs
Comparator / control treatment
Placebo tablets for oral administration will be matched in appearance to SIR9900 tablets and supplied at a dosage strength of 10 mg. SIR9900 placebo tablets production process was that Lactose, Microcrystalline Cellulose, Croscarmellose sodium, Colloidal Silica Dioxide and Magnesium Stearate were blended and compressed to form tablets.
Control group
Placebo

Outcomes
Primary outcome [1] 335147 0
PART 2 (MAD)
To evaluate the safety and tolerability of ascending multiple oral doses of SIR9900 in healthy elderly participants by evaluating treatment emergent adverse events (TEAEs), 12-lead electrocardiogram (ECG) parameters, vital signs, and clinical laboratory evaluations.
Timepoint [1] 335147 0
1. AE's and Serious Adverse Events (SAE's) will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) and grouped by system organ class (SOC) and preferred terms (PT). AE's and SAE's will be continuously assessed as they are reported or observed and reviewed daily from post dose of Investigational product (IP) on Day 1 until the follow up visit on Day 21.

2. Single 12-lead ECG will be performed at all scheduled time points after at least 10 minutes supine at Screening, within 60mins pre-dose and within 3 hours post-dose on Day 1, Day 4, Day 7 and Day 10 then Day 14 and Day 21 (Follow-Up Visit).

3. Vital signs (Blood pressure, heart rate, tympanic temperature and respiratory rate) are assessed at the Screening Visit, Day -1, Days 1 -10 (within 60 minutes pre-dose and 3 hours post dose), then Day 11, Day 12, Day 13, Day 14 and Day 21 (Follow-Up Visit),
- Blood pressure will be assessed pre dose using a sphygmomanometer (blood pressure cuff ). Blood pressure readings will be collected in triplicate and will be measured with 1-3 min interval between readings at screening only. Blood pressure will be measured with participant in a sitting position for atleast5 minutes at screening, and participant in a supine position for at least 5 minutes at other visits
- Heart Rate will be assessed pre dose and post dose by counting the number of heart beats.
- Tympanic Temperature will be assessed pre dose and post dose using a tympanic thermometer.
- Respiratory rate will be assessed pre dose and post dose by observing the number of breaths a participant takes.

4. Clinical laboratory assessments (haematology, serum chemistry and coagulation) under fasted conditions will be collected via venepuncture at the Screening Visit and Day -1 (if required) and post-dose on Day 1, Day 4, Day 7, Day 10, Day 14 and Day 21 (Follow-Up Visit).

5. Clinical laboratory assessments (Urinalysis) will be tested using a urine dipstick at the CRU. Urinalysis will be performed at Screening Visit and Day -1 (if required) and post-dose on Day 1, Day4, Day 7, Day 10, Day 14 and Day 21 (Follow-Up Visit).
Secondary outcome [1] 423269 0
Part 2 (MAD)
To characterize the plasma pharmacokinetic (PK) profile of SIR9900 after ascending multiple oral doses in healthy elderly participants.

Following ascending multiple doses, parameters to be measured will include but not limited to:
Cmax,ss,
Cmin,ss,
Cavg,
Tmax,
t1/2,
AUCtau,
Lambda z,
CLss/F,
Vss/F,
DF,
ARAUC/AR Cmax.
Timepoint [1] 423269 0
Blood samples for Plasma pharmacokinetic (PK) will be collected via venepuncture on Day 1 pre-dose (within 30 minutes prior to dosing) then Day 1 (0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours post-dose). Days 2, 3, 4, 5,6, 7, 8 and Day 9 pre-dose (within 30 minutes prior to dosing) then at 3 hours post-dose. Day 10 pre-dose (within 30 minutes prior to dosing) and then (0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hrs post-dose). Day 11 (24 & 36hrs post-dose), Day 12 (48 & 60 hrs post-dose), Day 13 (72 hrs post-dose) and Day 14 (96hrs post-dose).
Secondary outcome [2] 423270 0
Part 2 (MAD) To characterize the pharmacodynamic (PD) profile of SIR9900 after ascending multiple oral doses in 30 mg healthy elderly participants.
Level of p RIPK1 proteins and possibly other biomarkers as deemed necessary.
Timepoint [2] 423270 0
Blood samples will be collected for pharmacodynamic (PD analysis) via venepuncture Day 1 and Day 7 pre-dose (within 30 minutes prior to dosing) and 3 hours post dose, Day 10 (3 hrs post-dose) Day 11 (24 hrs post dose), Day 3 (72 hrs post dose) and Day 14 (96 hrs post dose).

Eligibility
Key inclusion criteria
Potential participants must fulfil all the following inclusion criteria to be eligible for the study:
1. Are capable of signing the Participant Informed Consent Form (PICF) and complying with study procedures.
2. Male or female participants aged greater than or equal to 65 years old who are healthy or have managed, stabilised disease in the opinion of the Investigator for the healthy elderly volunteer cohort in Part 2 (MAD) only.
3. Women of childbearing potential (WOCBP) must agree to practice a double method of contraception of a medically acceptable method of contraception with an annual failure rate of less than 1% with a barrier contraceptive (such as condom) during the study and for 30 days after discontinuation of study treatment. Unless she is exclusively in same-sex relationships. Women are considered not of childbearing potential if they are surgically sterile (i.e., hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or > 1 year postmenopausal.
4. All male participants with female partners of childbearing potential must agree to practice a double method of contraception of a medically acceptable method of contraception with an annual failure rate of less than 1% with a barrier contraceptive (such as condom), and must agree to abstain from sperm donation during and for 90 days after participation in the study. Unless he is exclusively in same-sex relationships.
5. Considered healthy by the Principal Investigator (PI) or delegate, based on a detailed medical history, full physical examination, clinical laboratory tests, 12-lead ECG and vital signs.
6. Non-smoker/Social smoker, defined as not having smoked more than 5 cigarettes or equivalent per day in the last 3 months before screening. During screening till the end of the confinement period, participant must be able to and must agree to abstain from the use of nicotine/tobacco containing products. Positive result of cotinine screen at admission will be excluded.
7. Able to abstain from the consumption of alcohol and any alcohol-containing products from 48 hours before dosing to the end of the confinement period
8. Able to abstain from the consumption of coffee and any caffeine-containing products from 48 hours before dosing to the end of the confinement period.
9. Body mass index (BMI) of 18 to 30 kg/m2 inclusive and body weight not less than 50 kg.
10. Willing and able to adhere to study restrictions and to be confined at the clinical research unit.
Minimum age
65 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Potential participants will be excluded from study entry if any of the following exclusion criteria are present at screening or admission:
1. Clinically significant haematological findings at screening.
2. Abnormal findings indicating hepatic impairment, such as aspartate transaminase (AST), alanine transaminase (ALT), or alkaline phosphatase greater than or equal to 1.5 times upper limit of normal (ULN), total bilirubin > ULN, albumin less than or equal to 3 g/dL, serum amylase or lipase greater than or equal to 1.5 times ULN at screening.
3. Abnormal findings indicating renal impairment, such as creatinine greater than or equal to 1.5 times ULN, estimated glomerular filtration rate of 80 mL/minute or less calculated by the Cockcroft-Gault formula, at screening.
4. Clinically significant ECG findings including QTcF value > 450 ms for male or > 470 ms for female at screening/pre-dose day 1.
5. Participants with a mean systolic blood pressure (SBP) of three measurements >140 mmHg, or a mean diastolic blood pressure (DBP) of three measurements > 90 mmHg at screening. Blood pressure will be measured at sitting position at screening.
6. Positive blood screen for human immunodeficiency virus (HIV), or hepatitis B surface antigen (HbsAg), or hepatitis C virus (HCV), or syphilis at screening or at any time during the screening period pre-dose.
7. A history of seizure. However, a history of febrile seizure is allowed.
8. Positive results of pregnancy test at screening or admission. Pregnant or breast feeding, or planning to become pregnant, breast feed or donate ova during the study and within 30 days after the study.
9. A hospital admission or major surgery within 60 days prior to screening and/or planned surgery for the duration of the study and follow up period.
10. Receipt of any other investigational drug product within 30 days or 5 half-lives of the other investigational drug (whichever is longer) prior to dosing.
11. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-V) substance use disorders and alcohol abuse within 12 months prior to screening and/or positive alcohol breath test at screening or admission.
12. A positive result for drugs of abuse at screening or admission. One repeat test will be allowed if false positive is considered by the PI or designee.
13. An unwillingness or inability to comply with food and beverage restrictions during study participation, including consumption of grapefruit (or pomelo or start fruit) or grapefruit juice, Seville oranges, Seville orange marmalade or other products containing grapefruit, pomelo, star fruit or Seville oranges within 7 days before dosing and until final discharge from the CRU.
14. Donation or blood collection of more than 1 unit (approximately 450 mL) of blood (or blood products) or acute loss of blood during the 30 days prior to screening and/or planning to donate blood during the study and follow up period.
15. Continued stable use within three months prior to screening of prescription and non-prescription medications, vitamins, and supplements that are not potential index substrates for CYP450 isoform 1A2, or inhibitor/inducers of isoforms 3A4 or 2C8 enzymes, and are used to manage and stabilise existing conditions or diseases are permitted at the discretion of the Investigator. The following is not permitted prior to dosing: use of prescription medicines or other products that are potential index substrates for CYP450 isoform 1A2, or inhibitor/inducers of isoforms 3A4 or 2C8 enzymes within 14 days, or within 5 half-lives (whichever is longer).
17. A history of suicide attempt in the past 12 months and/or judged by the Investigator as having a significant history of risk of suicide or homicide.
18. Participant has a known or suspected hypersensitivity to SIR9900 and any components of the SIR9900 (or placebo) tablets.
19. Participant who has lactose intolerance history.
20. Participant has any other condition which makes the participant unsuitable for study participation in the opinion of the Investigator.
21. Identified as a site employee of the Investigator or study centre, with direct involvement in the proposed study or other studies under the direction of the Investigator or study centre, and/or is an immediate family member (i.e., spouse, de facto, child) of site employees or Investigator.

Additional Exclusion Criteria:
In addition to the general criteria above, potential participants for the MAD Elderly cohort must not meet the following exclusion criteria:
1. If aged greater than or equal to 65 years, has any history or evidence 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 judged by the Investigator or designee.
2. (Replacement for general exclusion criterion #3) If aged greater than or equal to 65 years, has an Estimated Glomerular Filtration Rate (calculated based on Cockcroft-Gault formula) < 60 mL/min.

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 randomised to receive active treatment or Placebo according to the randomisation schedule and plan prepared prior to study start. Code-break tamper-evident envelopes containing treatment allocation per participant will be provided to the study site for emergency unblinding if required.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomised on Day -1 or Day 1 via permuted block randomisation ( to account for sentinels and the Rest of cohort ratio allocation) and then printed on randomisation list to receive either SIR9900 or placebo at a ratio of 4:1 (8 active: 2 Placebo) for Part 2 MAD Cohort 5.
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
Approximately 10 healthy elderly participants in MAD cohort 5 of Part 2 with 8 participants randomised to receive an oral dose of SIR9900 once daily (QD) for 10 consecutive days and 2 to receive an oral dose of placebo once daily for 10 consecutive days.

After the SRC favourable review of first 2 cohorts of Part 1 SAD, Part 2 (MAD) of the study may commence when safety and tolerability is satisfying and full PK data emerging from Part 1 (SAD) indicate that, following repeat dosing, the proposed Part 2 starting dose of 3 mg is predicted to result in a steady state exposure which does not exceed the exposure shown to be safe following a single dose.

The MAD cohort 5 (healthy elderly volunteers, 30 mg) will proceed after SRC review of MAD cohort 3 (healthy adults, 30 mg), and so may overlap with MAD cohort 4 (60 mg).
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
The study is the first in human study with SIR9900 and as such no formal sample size calculation was performed. The chosen sample size is deemed adequate to evaluate all study endpoints.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
20/11/2023
Actual
4/12/2023
Date of last participant enrolment
Anticipated
Actual
4/12/2023
Date of last data collection
Anticipated
Actual
28/12/2023
Sample size
Target
10
Accrual to date
Final
8
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 24966 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 40619 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 314127 0
Commercial sector/Industry
Name [1] 314127 0
Sironax Aus Pty Ltd
Country [1] 314127 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Sironax Aus Pty Ltd
Address
Level 40, 2-26 Park Street, Sydney, NSW 2000
Country
Australia
Secondary sponsor category [1] 316044 0
Commercial sector/Industry
Name [1] 316044 0
Avance Clinical Pty Ltd
Address [1] 316044 0
213 Glynburn Road
Firle SA 5070
Country [1] 316044 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313263 0
Alfred Hospital HREC
Ethics committee address [1] 313263 0
Ethics committee country [1] 313263 0
Australia
Date submitted for ethics approval [1] 313263 0
03/05/2023
Approval date [1] 313263 0
01/06/2023
Ethics approval number [1] 313263 0
HREC/97490/Alfred-2023

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

Contacts
Principal investigator
Name 127526 0
Dr Ofer Gonen
Address 127526 0
Nucleus Network Melbourne
Level 5, Burnet Tower, 89 Commercial Rd, Melbourne 3004, VIC
Country 127526 0
Australia
Phone 127526 0
+61 431 614 515
Fax 127526 0
Email 127526 0
o.gonen@nucleusnetwork.com.au
Contact person for public queries
Name 127527 0
Ofer Gonen
Address 127527 0
Nucleus Network Melbourne
Level 5, Burnet Tower, 89 Commercial Rd, Melbourne 3004, VIC
Country 127527 0
Australia
Phone 127527 0
+61 431 614 515
Fax 127527 0
Email 127527 0
o.gonen@nucleusnetwork.com.au
Contact person for scientific queries
Name 127528 0
Ofer Gonen
Address 127528 0
Nucleus Network Melbourne
Level 5, Burnet Tower, 89 Commercial Rd, Melbourne 3004, VIC
Country 127528 0
Australia
Phone 127528 0
+61 431 614 515
Fax 127528 0
Email 127528 0
o.gonen@nucleusnetwork.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Privacy and intellectual considerations.


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.