Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000696695
Ethics application status
Approved
Date submitted
22/05/2023
Date registered
30/06/2023
Date last updated
4/10/2023
Date data sharing statement initially provided
30/06/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A Randomized, Double-Blind and Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SIR9900 after Oral Administrations in Healthy Adult Volunteers
Scientific title
A Randomized, Double-Blind and Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SIR9900 after Oral Administrations in Healthy Adult Volunteers
Secondary ID [1] 309511 0
SIR9900-AU-101
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Inflammatory diseases, particularly in central nervous system 329794 0
Degenerative diseases, particularly in central nervous system. 329795 0
Condition category
Condition code
Inflammatory and Immune System 326689 326689 0 0
Other inflammatory or immune system disorders
Neurological 326690 326690 0 0
Neurodegenerative diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part 1: SAD. Participants will receive 1 dose of either SIR9900 or placebo as an oral tablet on Day 1. A total of approximately 80 healthy participants are planned to be enrolled. Approximately 40 healthy adult participants in 5 cohorts in Part 1 (8 participants per cohort), with 6 randomised to receive a single oral dose of SIR9900 and 2 to receive placebo.

The following dose level cohorts are planned with all cohorts to be randomised to receive either SIR990 or placebo:
• Cohort 1: 3 mg
• Cohort 2: 10 mg
• Cohort 3: 30 mg (SAD cohort 3 is also FE cohort period 1)
• Cohort 4: 100 mg
• Cohort 5: 200 mg

During the treatment period of Part 1 SAD study, participants will remain admitted to the Clinical Research Unit (CRU) from Day 1 until Day 5 .

Participants enrolled in cohort 3 (30 mg cohort) will be readmitted to the CRU on Day 9 (+1) (period 2) to receive a second dose on Day 10 after a washout period of 9 days as part of the Food Effect study.

Part 2: MAD. Approximately 40 healthy adult participants in 4 cohorts in Part 2 (10 participants per cohort) 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 cohorts are planned:
• Cohort 1 (healthy adults): 3 mg
• Cohort 2 (healthy adults): 10 mg
• Cohort 3 (healthy adults): 30 mg
• Cohort 4 (healthy adults): 60 mg

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 strengths 3 mg, 10 mg, and 50 mg.

Adherence to Intervention will be managed via recording in appropriate drug accountability records.
Intervention code [1] 325943 0
Treatment: Drugs
Comparator / control treatment
Placebo tablets for oral administration will be matched in appearance to SIR9900 tablets and supplied at 3 mg, 10 mg, and 50 mg dosage strengths. 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] 334556 0
PART 1 (SAD)
To evaluate the safety and tolerability of ascending single oral doses of SIR9900 in healthy participants by evaluating treatment emergent adverse events (TEAEs), 12-lead electrocardiogram (ECG) parameters, vital signs, and clinical laboratory evaluations.
Timepoint [1] 334556 0
1. Adverse Event's (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 12.

2. Vital signs (Blood pressure, heart rate, tympanic temperature and respiratory rate) are assessed at the Screening Visit, Day -1 and Day 1 pre-dose (within 60 minutes prior to dosing) then Day 1 (0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 & 12 hrs post-dose), Day 2 (24 & 36 hrs post-dose), Day 3 (48 & 60 hrs post-dose), Day 4 (72 hrs post-dose), Day 5 (96 hrs post-dose) and Day 12 (Follow up Visit), post-commencement of intervention.
- 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 at least 5 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.

3. Single 12-lead ECG will be performed at all scheduled time points after at least 10 minutes supine on Day 1 pre-dose (within 60 minutes prior to dosing) and then Day 1 (0.5, 1, 2, 3, 4, 6 and 12 hours post-dose), Day 2 (24hrs post-dose), Day 3 (48hrs post-dose), Day 4 (72hrs post-dose), Day 5 (96 hrs post-dose). The recommended order for assessments required at the same time point is ECG, vital signs, blood collection.

4. Clinical laboratory assessments (haematology, serum chemistry and coagulation) under fasted conditions will be collected via venepuncture at the Screening Visit, Day -1 (if required), Day 1 (2 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose), Day 4 (72 hrs post-dose), Day 5 (96 hrs post-dose) and at Day 12 (Follow Up Visit) post-commencement of intervention.

5. Clinical laboratory assessments (Urinalysis) will be tested using a urine dipstick at the CRU. Urinalysis will be performed at Screening Visit, Day -1 (if required), Day 1 (2 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose), Day 4 (72 hrs post-dose), Day 5 (96 hrs post-dose) and at Day 12 (Follow Up Visit) post-commencement of intervention.
Primary outcome [2] 334774 0
PART 1 SAD Cohort 3 - Food Effect (FE)
To evaluate the safety and tolerability of ascending single oral doses of SIR9900 in healthy participants by evaluating treatment emergent adverse events (TEAEs), 12-lead electrocardiogram (ECG) parameters, vital signs, and clinical laboratory evaluations.
Timepoint [2] 334774 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 Day 21 (Follow-Up Visit).

2. Vital signs (Blood pressure, heart rate, tympanic temperature and respiratory rate) are assessed at the Screening Visit, Day -1 and Day 1 pre-dose (within 60 minutes prior to dosing), then Day 1 (0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 & 12 hrs post-dose), Day 2 (24 & 36 hrs post-dose), Day 3 (48 & 60 hrs post-dose), Day 4 (72 hrs post-dose), Day 5 (96 hrs post-dose), Day 9 (pre-second dose), Day 10, (pre-second dose) and then Day 10 (0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 &12 hrs post-second dose), Day 11 (24 & 36 hrs post-second dose), Day 12 (48 & 60 hrs post-second dose), Day 13 (72 hrs post-second dose), Day 14 (96 hrs post-second dose) and Day 21 (post-last dose 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 at least5 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.

3. Single 12-lead ECG will be performed at all scheduled time points after at least 10 minutes supine Day 1 pre-dose (within 60 minutes prior to dosing) and then Day 1 (0.5, 1, 2, 3, 4, 6 and 12 hours post-dose), Day 2 (24hrs post-dose), Day 3 (48hrs post-dose),Day 4 (72hrs post-dose), Day 5 (96 hrs post-dose), Day 10 (pre-second dose) and then Day 10 (0.5, 1, 2, 3, 4, 6 and 12 hours post-second dose), Day 11 (24hrs post-second dose), Day 12 (48hrs post-second dose), Day 13 (72hrs post-second dose), Day 14 (96 hrs post-second dose) and Day 21 (post-last dose Follow-Up Visit). The recommended order for assessments required at the same time point is ECG, vital signs, blood collection.

4. Clinical laboratory assessments (haematology, serum chemistry and coagulation) under fasted and fed conditions, will be collected via venepuncture at the Screening Visit and Day -1 (if required), Day 1 (2 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose), Day 4(72 hrs post-dose), Day 5 (96 hrs post-dose), Day 9 (pre-second dose) Day 10 under fed conditions (2 hrs post-second dose), Day11 (24 hrs post-second dose), Day 12 (48 hrs post-second dose), Day 13 (72 hrs post-second dose), Day 14(96 hrs post-second dose), and Day 21 (post-last dose 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(, Day 1 (2 hrs post-dose), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-dose), Day 4 (72 hrs post-dose), Day 5 (96 hrs post-dose), Day 9 (pre-second dose) Day 10 (2 hrs post-second dose), Day 11 (24 hrs post-second dose), Day 12(48 hrs post-second dose), Day 13 (72 hrs post-second dose), Day 14 (96 hrs post-second dose), and Day 21 (Follow-Up Visit).
Primary outcome [3] 334775 0
PART 2 (MAD)
To evaluate the safety and tolerability of ascending multiple oral doses of SIR9900 in healthy participants by evaluating treatment emergent adverse events (TEAEs), 12-lead electrocardiogram (ECG) parameters, vital signs, and clinical laboratory evaluations.
Timepoint [3] 334775 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 at least5 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] 422038 0
Part 1 (SAD)
To characterize the plasma pharmacokinetic (PK) profile of SIR9900 after ascending single oral doses in healthy participants.

Plasma PK parameters following ascending single doses including but not limited to:
Cmax,
Tmax,
AUC0-24h,
AUClast,
CL/F,
Vd/F.
Timepoint [1] 422038 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 and 12 hrs post-dose), Day 2 (24 & 36 hrs post-dose), Day 3 (48 & 60 hrs post-dose), Day 4 (72 hrs post-dose), Day 5 (96 hrs post-dose).
Secondary outcome [2] 422039 0
Part 1 Cohort 3 Food Effect (FE)
To characterize the plasma pharmacokinetic (PK) profile of SIR9900 after ascending single oral doses in healthy participants in a fasted state.

Plasma PK parameters following ascending single doses including but not limited to:
Cmax,
Tmax,
AUC0-24h,
AUClast,
t1/2,
AUCinf,
Lambda z,
CL/F,
Vd/F.
Timepoint [2] 422039 0
Blood samples for Plasma pharmacokinetic (PK) under fasted and fed conditions, 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 hrs post-dose), Day 2 (24 & 36 hrs post-dose), Day 3 (48 & 60 hrs post-dose), Day 4 (72 hrs post-dose), Day 5 (96 hrs post-dose), Day 9 (pre-second dose), pre-second dose on Day 10 (0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 & 12 hrs post-second dose), Day 11 (24 & 36hrs post-second dose), Day 12 (48 & 60 hrs post-second dose), Day 13 (72 hrs post-second dose), Day 14 (96 hrs post-second dose).
Secondary outcome [3] 422040 0
Part 2 (MAD)
To characterize the plasma pharmacokinetic (PK) profile of SIR9900 after ascending multiple oral doses in healthy 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 [3] 422040 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 & 36 hrs post-dose),Day 12 (48 & 60 hrs post-dose), Day 13 (72 hrs post-dose) and Day 14 (96hrs post-dose).
Secondary outcome [4] 422041 0
Part 1 (SAD)
To characterize the urine PK profile of SIR9900 after single oral doses of 30 mg and 100 mg in healthy participants.

Urine PK parameters following single 30 mg and 100 mg doses including but not limited to: Ae(0-t),
fe,24%,
CLr.
Timepoint [4] 422041 0
Urine samples for pharmacokinetic (PK) analysis will be collected Day 1 pre-dose (within 60 minutes prior to dosing) from each participant in the 30 mg cohorts. Urine samples for PK analysis will be collected again during the 0-4, 4-8,8-12, 12-24, 24-48, 48-72 and 72-96 hour periods post-dose (all urine to be collected for each period).
Secondary outcome [5] 422042 0
Part 1 Cohort 3 Food Effect (FE)
To characterize the urine PK profile of SIR9900 after single oral doses of 30 mg in healthy participants (Period 1 only).

Urine PK parameters following single 30 mg doses including but not limited to:
Ae(0-t),
fe,24%,
CLr.
Timepoint [5] 422042 0
Urine samples for pharmacokinetic (PK) analysis will be collected in Period 1 only, Day 1 pre-dose (within 60 minutes prior to dosing) from each participant in the 30 mg cohorts. Urine samples for PK analysis will be collected again during the 0-4, 4-8, 8-12, 12-24, 24-48, 48-72 and 72-96 hour periods post-dose (all urine to be collected for each period).
Secondary outcome [6] 422043 0
Part 1 (SAD)
To characterize the pharmacodynamic (PD) profile of SIR9900 after ascending single oral doses in healthy participants.

Level of p-RIPK1 proteins and possibly other biomarkers as deemed necessary.
Timepoint [6] 422043 0
Blood samples will be collected for pharmacodynamic (PD analysis) via venepuncture Day 1 pre-dose (within 30 minutes prior to dosing) and 3 hours post dose, Day 2 (24 hrs post-dose), Day 4 (72 hrs post-dose) and Day 5 (96 hrs post-dose).
Secondary outcome [7] 422044 0
Part 1 Cohort 3 Food Effect (FE)
To characterize the pharmacodynamic (PD) profile of SIR9900 after a single 30 mg dose in healthy participants (Period 1 only)

Level of p-RIPK1 proteins and possibly other biomarkers as deemed necessary.
Timepoint [7] 422044 0
Blood samples will be collected for pharmacodynamic (PD analysis) in period 1 only, via venepuncture Day 1 pre-dose (within 30 minutes prior to dosing) and 3 hours post dose, Day 2 (24 hrs post-dose), Day 4 (72 hrs post-dose) and Day 5 (96 hrs post-dose).
Secondary outcome [8] 422045 0
Part 2 (MAD) To characterize the pharmacodynamic (PD) profile of SIR9900 after ascending multiple oral doses in 3mg adult healthy participants. Level of p RIPK1 proteins and possibly other biomarkers as deemed necessary.
Timepoint [8] 422045 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).
Secondary outcome [9] 422046 0
Part 1 Cohort 3 Food Effect (FE)
To evaluate the preliminary food effect on PK profile of a single 30 mg dose of SIR9900 in a fed state.

Following a single 30 mg dose of SIR9900: Plasma PK Parameters to be measured will include but not limited to:
Cmax,
Tmax,
AUCinf,
AUClast,
t1/2,
Lambda z,
CL/F,
Vd/F.
Timepoint [9] 422046 0
Blood samples for Plasma pharmacokinetic (PK) will be collected under fasted and fed conditions via venepuncture Day 1 pre-dose (within 30 minutes prior to dosing) and then Day 1 (0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose), Day 2 (24 & 36 hrs post-dose), Day 3 (48 & 60 hrs post-dose), Day 4 (72 hrs post-dose), Day 5 (96 hrs post-dose), Day 10 pre-second dose and then Day 10 (0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 & 12 hrs post-second dose), Day 11 (24 & 36 hrs post-second dose), Day 12 (48 & 60 hrs post-second dose), Day 13 (72 hrs post-second dose), Day 14 (96 hrs post-second dose).
Secondary outcome [10] 422047 0
Exploratory Objective - Part 1 (SAD)
To explore the metabolite identification of SIR9900 in urine after a single 30 mg and/or 100 mg dose ofSIR9900.

Identification of SIR9900 metabolites and semi-quantification of SIR9900 in urine after a single 30 mg and/or 100 mg dose.
Timepoint [10] 422047 0
Urine samples for analysis will be collected Day 1 pre-dose (within 60 minutes prior to dosing) from each participant in the 30 mg and 100mg cohorts. Urine samples for analysis will be collected again during the 0-4, 4-8, 8-12, 12-24, 24-48, 48-72and 72-96 hour periods post-dose. Urine collections could also be used for identification of metabolites.
Secondary outcome [11] 422048 0
Exploratory Objective - Part 1 Cohort 3 Food Effect (FE)
To explore the metabolite identification of SIR9900 in urine after a single 30 mg dose of SIR9900.

Identification of SIR9900 metabolites and semi-quantification of SIR9900 in urine after a single 30 mg dose. Period 1 only.
Timepoint [11] 422048 0
Urine samples will be collected for analysis in Period 1 only, Day 1 pre-dose (within 60 minutes prior to dosing) from each participant. Urine samples analysis will be collected again during the 0-4, 4-8, 8-12, 12-24, 24-48, 48-72 and 72-96 hour periods post-dose. Urine collections could also be used for identification of metabolites.
Secondary outcome [12] 422049 0
Part 2 (MAD)
To measure the cerebrospinal fluid (CSF) concentration of SIR9900 after multiple oral doses of 30 mg in healthy adult participants.

CSF concentration of SIR9900 following multiple oral doses of 30 mg.
Timepoint [12] 422049 0
A CSF sample of approximately 10 mL will be collected from each participant in Part 2 MAD Cohort 3. The CSF sample will be collected once between the Days of 6 to 9 and between 3 to 7 hours post-dose. One additional blood sample should be collected within 15 minutes after CSF sampling to determine the drug concentration relationship between CSF and blood.
Secondary outcome [13] 422050 0
Exploratory Objective - Part 2 (MAD) To explore the metabolite identification of SIR9900 in plasma after multiple doses of 30 mg in healthy adult participants. Identification of SIR9900 metabolites and semi-quantification of SIR9900 in plasma after 30mg multiple doses in healthy adult participants.
Timepoint [13] 422050 0
Blood plasma samples to help with the identification of metabolites in the 30 mg and/or 100 mg cohorts in the future will be collected Day 1 pre-dose (within 30 minutes prior to dosing) and then Day 1, (0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hrs post-dose). Days 2 to 9 pre-dose (within 30 minutes prior to dosing and 3 hrs post-dose, Day 10 pre-dose (within 30 minutes prior to dosing) and then Day 10 (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).

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 healthy participants between the ages of 18 and 64 years old, inclusive, for healthy adult volunteer cohorts.
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 percent 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 tubal ligation) or greater than 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 percent 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
18 Years
Maximum age
64 Years
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 greater than 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/1.73m2 or less calculated by the Cockcroft-Gault formula, at screening.
4. Clinically significant ECG findings including QTcF value greater than 450 ms for male or greater than 470 ms for female at screening/pre-dose day 1.
5. Participants with a mean systolic blood pressure (SBP) of three measurements greater than 140 mmHg, or a mean diastolic blood pressure (DBP) of three measurements greater than 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) 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, lactating, 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. For participants aged up to and including 64 years, use of prescription or non-prescription drugs (contraceptives are permitted), including vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days, or 14 days if the drug is a potential index substrate for CYP450 isoform 1A2, or inhibitor/inducer of isoforms 3A4 or 2C8 enzymes, or 5 half- lives (whichever is longer) prior to dosing. These medications are also prohibited during the study except for those permitted, such as hormonal contraception.
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).
16. 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.
17. Participant has a known or suspected hypersensitivity to SIR9900 and any components of the SIR9900 (or placebo) tablets.
18. Participant who has lactose intolerance history.
19. Participant has any other condition which makes the participant unsuitable for study participation in the opinion of the Investigator.
20. 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 adult participants (aged 18-64 years, inclusive) must not meet the following exclusion criterion:
1. Participant 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, as judged by the Investigator or designee. Fully resolved childhood asthma and fully resected basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) with no reoccurrence, and all above with no medication taken is permitted.

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 randomized to receive active treatment or Placebo according to the randomization 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 randomized 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 3:1 (6 active: 2 Placebo) for Part 1 SAD and a ratio of 4:1 (8 active: 2 Placebo) for Part 2 MAD.
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
A total of approximately 80 healthy participants are planned to be enrolled. Approximately 40 healthy adult participants in 5 cohorts in Part 1 (8 participants per cohort), with 6 randomised to receive a single oral dose of SIR9900 and 2 to receive placebo.

Approximately 40 healthy adult participants in 4 cohorts in Part 2 (10 participants per cohort) 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.

Evaluation of dose levels will be conducted in a sequential fashion with lower dose levels evaluated first in the sequence. 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.
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
Recruiting
Date of first participant enrolment
Anticipated
3/07/2023
Actual
3/07/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
80
Accrual to date
33
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 24597 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 40195 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 313705 0
Commercial sector/Industry
Name [1] 313705 0
Sironax Aus Pty Ltd
Country [1] 313705 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] 315513 0
Commercial sector/Industry
Name [1] 315513 0
Avance Clinical
Address [1] 315513 0
213 Glynburn Road
Firle SA 5070
Country [1] 315513 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312878 0
Alfred Hospital HREC
Ethics committee address [1] 312878 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 312878 0
Australia
Date submitted for ethics approval [1] 312878 0
03/05/2023
Approval date [1] 312878 0
01/06/2023
Ethics approval number [1] 312878 0
HREC/97490/Alfred-2023

Summary
Brief summary
This will be a single-centre, randomised, double-blind, placebo-controlled, and sequential cohort study to evaluate the safety, tolerability, PK and PD of single and multiple ascending doses of SIR9900 after oral administrations in healthy adult volunteers.

Male and female healthy adult volunteers aged 18 to 64 years inclusive at the time of screening are eligible for recruitment.

Part 1 SAD participants (except cohort 3) will have a screening period of up to 28 days and be required on-study for approximately 2 weeks post-dose. Part 1 SAD cohort 3 (FE) and Part 2 MAD participants will have a screening period of up to 28 days and be required on-study for approximately 3 weeks post-dose.

SIR9900 is a potent and selective allosteric RIPK1 inhibitor being developed for the potential treatment of inflammatory, autoimmune, and degenerative diseases, particularly in the central nervous system.
Trial website
Trial related presentations / publications
Public notes
Exclusion Criteria
6. Positive nasopharynx swab test for SARS-CoV-2 (or any other test for Corona virus disease 2019 [COVID-19]) at any time during the screening period pre-dose.
21. Use of vaccines (including COVID-19 vaccine) within 14 days prior to dosing or planned vaccination during the study.

Contacts
Principal investigator
Name 126190 0
Dr Ofer Gonen
Address 126190 0
Nucleus Network Melbourne
Level 5, Burnet Tower, 89 Commercial Rd, Melbourne 3004, VIC
Country 126190 0
Australia
Phone 126190 0
+61 431 614 515
Fax 126190 0
Email 126190 0
[email protected]
Contact person for public queries
Name 126191 0
Dr Ofer Gonen
Address 126191 0
Nucleus Network Melbourne
Level 5, Burnet Tower, 89 Commercial Rd, Melbourne 3004, VIC
Country 126191 0
Australia
Phone 126191 0
+61 431 614 515
Fax 126191 0
Email 126191 0
[email protected]
Contact person for scientific queries
Name 126192 0
Dr Ofer Gonen
Address 126192 0
Nucleus Network Melbourne
Level 5, Burnet Tower, 89 Commercial Rd, Melbourne 3004, VIC
Country 126192 0
Australia
Phone 126192 0
+61 431 614 515
Fax 126192 0
Email 126192 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
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.