Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001621808
Ethics application status
Approved
Date submitted
29/10/2021
Date registered
29/11/2021
Date last updated
29/04/2024
Date data sharing statement initially provided
29/11/2021
Date results provided
29/04/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A Study to Investigate the Safety of SIR2446M in Healthy Volunteers
Scientific title
A Randomized, Double-Blind and Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SIR2446M after Oral Administrations in Healthy Volunteers
Secondary ID [1] 305659 0
SIR2446M-AU-101
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Degenerative disease 324142 0
Inflammatory disease 324143 0
Condition category
Condition code
Inflammatory and Immune System 321616 321616 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
RIP1 mediates the downstream effects of multiple biological activities including inflammatory responses. Therefore RIP1 inhibitors may be advantageous over selective inhibitors for a specific cytokine to reduce inflammatory response. SIR2446M is a Receptor-Interacting Protein1 (RIP1) inhibitor that is under development as a new investigational drug for the treatment of inflammatory diseases such as Alzheimer's disease and Multiple Sclerosis.

This is a two part, double-blind, randomised and placebo-controlled study to evaluate safety, tolerability, pharmacokinetics and pharmacodynamics of an oral capsule or oral tablet dose of SIR2446M in healthy volunteers. Part 1 will be a single ascending dose (SAD) design to assess single doses of the study drug with and without food. All participants except those in the food-effect group will receive either placebo or the study drug in capsule form. Part 2 will be a multiple ascending dose(MAD) design to assess multiple doses of the study drug. Participants in the MAD groups will receive either placebo or study drug in oral tablet form. Participants in the food effect group will receive the study drug in oral tablet form.

In Part 1, 56 participants will receive either study drug or matched placebo at one of seven dose levels (3mg, 10mg, 30mg, 100mg, 200mg, 400mg, or 600mg). Participants will stay to complete safety assessments up to 72 hours post dose, and then return to the clinical site on Day 11 (±3 days) for follow up assessments. These groups will receive a single dose only.

There will be a separate food-effect cohort of 8 participants receiving 100mg tablet, who will receiving study drug on D1 then stay to complete safety assessments up to 72 hours post dose. The participants will return on Day 7 (+1 day) for a second dosing period at the same dose level following a high-fat, high-calorie breakfast. This breakfast will be provided to the participants. They will check out once the +72 hour safety assessments have been completed, and return on Day 18 (±3 days) for follow up assessments.

In Part 2, 50 participants will receive either the study drug or the matched placebo once a day for 10 days at one of five dose levels (5 mg, 30mg, 100mg, 200mg or 400mg). Participants will stay until Day 13 for safety assessments, and return on day 20 (±3 days) for their follow up assessments.

In both parts of the study, trained nurses will be administering the study drugs to the participants.
Intervention code [1] 322070 0
Treatment: Drugs
Comparator / control treatment
Placebo capsule which is an excipient match to the SIR2446M capsule. The placebo capsule contains microcrystalline cellulose (MCC). Capsules administered to the SAD cohorts.

Placebo tablet which is an excipient match to the SIR2446M tablet. Tablets administered to the MAD cohorts.
Control group
Placebo

Outcomes
Primary outcome [1] 329382 0
To evaluate overall safety and tolerability of SIR2446M after single ascending doses (SAD) administered orally in healthy participants. Safety assessments include monitoring of adverse events, physical examinations, 12-lead ECG parameters, vital signs and clinical abnormalities data after single oral doses.

Examples of adverse events include headache, fatigue and dizziness. These will be reported by the participant to study site staff, Open-ended and non-leading verbal questioning of the participant will be used to inquire about AE occurrences.
Timepoint [1] 329382 0
Adverse events will be monitored throughout the study, this will be Day 1 to Day 11 inclusive for all Part 1 groups, The food-effect group will be monitored from Day 1 to Day 18 inclusive. For all groups, adverse event monitoring will be continuous.
Primary outcome [2] 329383 0
To evaluate the safety and tolerability of SIR2446M after multiple ascending doses (MAD) administered orally in healthy participants. Safety assessments include AEs, physical examination, 12-lead ECG parameters, vital signs and clinical abnormalities data after multiple escalating oral doses.

Examples of adverse events include headache, fatigue and dizziness. These will be reported by the participant to study site staff, Open-ended and non-leading verbal questioning of the participant will be used to inquire about AE occurrences. Investigators will then categorise the adverse events as Mild, Moderate or Severe.
Timepoint [2] 329383 0
Adverse events will be assessed throughout the study from Day 1 to Day 20 inclusive. For all groups, adverse event monitoring will be continuous.

Full physical examination will be conducted at screening only, abbreviated physical examination at Day-1, Day 13 and symptom directed physical examination will be conducted on Day 20
ECGs will be conducted at screening, Day -1, Day 1, 4, 7, 10, 13, and on Day 20.
Vital signs will be conducted at screening, daily from Day -1 to Day 13, and on Day 20.
Secondary outcome [1] 402398 0
To characterize the PK profile of SIR2446M after single escalating oral doses in healthy participants. The primary PK parameters of interest include Cmax, Tmax, t1/2, AUC0-24h, AUClast, AUCinf, Lambda-z, CL/F and Vd/F for plasma.
Timepoint [1] 402398 0
For all SAD groups, PK blood samples taken predose, at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 60 and 72 hours post dose. For the food-effect group, PK blood samples taken predose, at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 60 and 72 hours post dose during their second inpatient stay (Day 7 to Day 11). For cohort 3,4 and 5, PK urine collection will occur predose, and during the 0-4, 4-8, 8-12, 12-24, 24-48, and 48-72 hours after the dose.
Secondary outcome [2] 402399 0
To explore the metabolite identification and biomarker of SIR2446M in urine after single dose.
Timepoint [2] 402399 0
PK urine collection will occur predose, and during the 0-4, 4-8, 8-12, 12-24, 24-48, and 48-72 hours after the dose.
Secondary outcome [3] 402400 0
To characterize the PK profile of SIR2446M after escalating multiple oral doses in healthy participants;
The primary PK parameters of interest include Cmax,ss, Cmin,ss, Cavg, Tmax, t1/2, AUCtau, Lambda-z, CLss/F, Vss/F, DF, ARAUC/ARCmax for blood plasma.
The primary PK parameters of interest include Ae, CLr and fe for urine.
Timepoint [3] 402400 0
On Day 1: Pre-dose (within 1 h prior to dosing), 0.25, 0.5, 1 (± 2 min), 2, 3, 4, 6 (± 5 min), 8, 10, 12 (± 10 min) hours post dose. On Days 2-9: Pre-dose (within 1 h prior to dosing), 3h (± 5 min) post dose. On Days 10-13: Pre-dose (within 1 h prior to dosing), 0.25, 0.5, 1 (± 2 min), 2, 3, 4, 6 (± 5 min), 8, 10, 12 (± 10 min), 24, 36, 48, 60 and 72 (± 30 min) hours post dose.
Secondary outcome [4] 402401 0
To characterize the PD profile of SIR2446M after escalating multiple oral doses in healthy participants. This information will be collected from blood samples provided during the study.
Timepoint [4] 402401 0
On Day 1: Pre-dose (within 1 h prior to dosing), 3 h, 6 h (± 5 min) post dose. On Day 2: Pre-dose (within 1 h prior to dosing). On Day 5: Pre-dose (within 1 h prior to dosing), 3 h (± 5 min) post dose. On Day 10: Pre-dose (within 1 h prior to dosing), 3 h, 6 h (± 5 min), and 24 h (± 30 min) post dose.
Secondary outcome [5] 402402 0
To explore the metabolite identification and biomarker of SIR2446M in plasma after multiple doses
Timepoint [5] 402402 0
in the second MAD cohort (200mg cohort) seminal plasma samples will be taken at 2h to 5h post dose on day 10. In case of operation challenges, within 10h of post dose is acceptable.
Secondary outcome [6] 406683 0
To compare the PK profile of SIR2446M in capsule and tablet after a single dose. The primary PK parameters of interest include Cmax,ss, Cmin,ss, Cavg, Tmax, t1/2, AUCtau, Lambda-z, CLss/F, Vss/F, DF, ARAUC/ARCmax for blood plasma..
Timepoint [6] 406683 0
For all SAD groups, PK blood samples taken predose, at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 60 and 72 hours post dose. For the food-effect group, PK blood samples taken predose, at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 60 and 72 hours post dose during their second inpatient stay (Day 7 to Day 11).
Secondary outcome [7] 406684 0
To evaluate the preliminary food effect on PK profile of SIR2446M tablet after single dose. The primary PK parameters of interest include Cmax,ss, Cmin,ss, Cavg, Tmax, t1/2, AUCtau, Lambda-z, CLss/F, Vss/F, DF, ARAUC/ARCmax for blood plasma.
Timepoint [7] 406684 0
PK blood samples taken predose, at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 60 and 72 hours post dose. PK blood samples taken predose, at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 60 and 72 hours post dose during their second inpatient stay (Day 7 to Day 11).

Eligibility
Key inclusion criteria
1. Are capable of signing informed consent form (ICF) and complying with study procedures;
2. Male or female healthy participants between the ages of 18 and 55 years old, inclusive;
3. Women of childbearing potential (WOCBP) must be practicing a medically acceptable method of contraception with an annual failure rate of less than 1% during the study and 30 days after discontinuation of study treatment. Women are considered not childbearing potential if they are more than 1 year postmenopausal or surgically sterile (ie, hysterectomy, bilateral oophorectomy, or bilateral salpingectomy tubal ligation).
4. All male patients with female partners of child-bearing potential must use two acceptable methods of contraception (one of which must be a barrier method), and must agree to abstain from sperm donation during and for 90 days after participation in the study.
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. Nonsmoker/Social smoker, defined as not having smoked more than 2 nicotine/tobacco containing products per month in the last 3 months before screening. During the study, participant should be able to abstain from the use of nicotine/tobacco containing products;
7. Able to abstain from the consumption of alcohol and any alcohol-containing products from 48 hours before dosing to the end of the study;
8. Able to abstain from the consumption of coffee and any caffeine-containing products from 48 hours before dosing to the end of the study;
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 center.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Clinically significant history of gastrointestinal, cardiovascular, musculoskeletal, endocrine, hematologic, psychiatric, renal, hepatic, bronchopulmonary, neurologic, immunologic, lipid metabolism disorders, or drug hypersensitivity;
2. Clinically significant hematological findings at screening;
3. Abnormal findings indicating hepatic impairment, such as AST, ALT, or alkaline phosphatase greater than or equal to 1.5 times upper limit of normal (ULN), total bilirubin greater than or equal to 2.0 times ULN, albumin less than or equal to 3 g/dL, serum amylase or lipase greater than or 1.5 times ULN at screening;
4. Abnormal findings indicating renal impairment, such as creatinine greater than or equal to
1.5 times ULN, estimated creatinine clearance of 80 mL/minute or less calculated by the Cockcroft-Gault formula at screening;
5. Clinically significant ECG findings such as QTc value greater than or equal to 450 ms for male or greater than or equal to 470 ms for female at screening/day -1; 6. Participants with a mean systolic blood pressure of three measurements greater than 140 mmHg, or a mean diastolic blood pressure of three measurements greater than 90 mmHg at screening. Blood pressure will be measured at sitting position at screening; 7. Known or suspected malignancy, except adequately treated basal cell carcinoma;
8. Positive blood screen for human immunodeficiency virus (HIV), or hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) or nasopharynx swab test for SARS-CoV-2 (or any other test for COVID);
9. A history of seizure. However, a history of febrile seizure is allowed;
10. Plan to become pregnant during the study and within 30 days after the study;
11. A hospital admission or major surgery within 60 days prior to screening;
12. Receipt of any other investigational drug product within 3 months or 5 half-lives (whichever is longer) prior to dosing;
13. DSM-V substance use disorders and alcohol abuse within 12 months prior to screening;
14. A positive result for alcohol or drugs of abuse at screening or admission. Repeat test will be allowed if false positive is considered by the PI or designee;
15. An unwillingness or inability to comply with food and beverage restrictions during study participation, consumption of grapefruit or grapefruit juice within 14 days before dosing and until completed follow up assessments;
16. Donation or blood collection of more than 1 unit (approximate 450 mL) of blood (or blood products) or acute loss of blood during the 30 days prior to screening;
17. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer or inhibitor) or 5 half-lives (whichever is longer) prior to dosing;
18. Use of vaccines (including COVID vaccine) within 7 days prior to dosing in SAD part and within 14 days prior to dosing in MAD part;
19. A history of suicide attempt in the past 12 months and/or seen by the Investigator as having a significant history of risk of suicide or homicide;
20. Participant has a known or suspected hypersensitivity toSIR2446M and any components of SIR2446M capsules or tablets;
21. Participant who has lactose intolerance history;
22. Participant has any other condition, which makes the participant unsuitable for study participation.

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)
All eligible subjects will be randomised using a central randomisation by computer model.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation 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
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
This is a phase 1 study, and therefore no statistical considerations were involved in the sample size determination for this study. It is expected that the sample size in each cohort should be adequate for evaluation of safety, PK and PD parameters.

Statistical analysis plan:
Safety data will be summarized using descriptive statistics for all participants who receive study drug or placebo. Data from all participants who receive placebo will be pooled.
AEs will be summarized by incidence rates for each treatment and analyzed descriptively.

Laboratory data will be summarized by presenting summary statistics of raw data and change from Baseline values, by presenting shift tables using clinically notable ranges (Baseline to most extreme post baseline value), and by flagging notable values in data listings. Clinically significant abnormal laboratory data will be listed for each participant.
Vital sign data (oral temperature, pulse, blood pressure and respiratory rate) will be summarized by presenting summary statistics for change from baseline values. The incidence rates of notable vital sign abnormalities will be summarized.
Values for 12-lead ECG parameters (HR, RR, PR, QRS, QT, and corrected QT interval with Fridericia formula) and change from Screening/Baseline values will be summarized through descriptive statistics by treatment group and visit. The number and percentage of participants with ECG findings will also be summarized by treatment group and visit. The maximum increase in corrected QT interval from Baseline will be summarized, and the frequencies of participants who fulfill the abnormal criteria based on the corrected QT interval will be calculated.

PK parameters will be summarized using descriptive statistics by dose level, day and treatment. Dose proportionality after administrations of SIR2446M will be assessed by fitting the natural log transformed exposure parameters (AUClast, AUCinf and Cmax) for all dose levels to a linear regression model: log(Y) = a+ ß log(X), where Y is PK parameter and X is dose. The slope will be estimated and presented along with the corresponding 90% confidence interval (CI).

Food effect will be assessed using Analysis of Variance (ANOVA). The dependent variable will be the log-transformed PK parameter of interest (AUClast, AUCinf, Cmax and Tlag) and the independent variables will include a fixed effect for treatment (with or without food) and a random participant effect. The estimated difference and confidence interval obtained on the log-scale will be exponentiated to provide an estimate of the food to fasted ratio and its associated 90% confidence interval.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
17/12/2021
Actual
17/12/2021
Date of last participant enrolment
Anticipated
19/12/2022
Actual
12/04/2023
Date of last data collection
Anticipated
1/02/2023
Actual
28/04/2023
Sample size
Target
114
Accrual to date
Final
114
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 20957 0
Linear Clinical Research - Nedlands
Recruitment hospital [2] 23702 0
Linear Clinical Research - Joondalup - Joondalup
Recruitment postcode(s) [1] 35786 0
6009 - Nedlands
Recruitment postcode(s) [2] 39137 0
6027 - Joondalup

Funding & Sponsors
Funding source category [1] 310018 0
Commercial sector/Industry
Name [1] 310018 0
Sironax Aus Pty Ltd
Country [1] 310018 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] 311072 0
None
Name [1] 311072 0
Address [1] 311072 0
Country [1] 311072 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309725 0
Bellberry Limited
Ethics committee address [1] 309725 0
Ethics committee country [1] 309725 0
Australia
Date submitted for ethics approval [1] 309725 0
21/10/2021
Approval date [1] 309725 0
17/11/2021
Ethics approval number [1] 309725 0

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

Contacts
Principal investigator
Name 115178 0
Dr Ana Liza Sun
Address 115178 0
Linear Clinical Research
1 Hospital Avenue, B-Block, 1st Floor,
Nedlands WA 6009
Country 115178 0
Australia
Phone 115178 0
+61 8 6382 5100
Fax 115178 0
Email 115178 0
asun@linear.org.au
Contact person for public queries
Name 115179 0
Bruce Lv
Address 115179 0
Sironax (Beijing) CO., Ltd
Room 2302, 23rd Floor, North Tower,
Jiazhaoye Plaza,
No 86 Jianguo Road,
Chaoyang district, Beijing, China
102206
Country 115179 0
China
Phone 115179 0
+86 15801188089
Fax 115179 0
Email 115179 0
bruce.lv@sironax.com
Contact person for scientific queries
Name 115180 0
Weiliang Fan
Address 115180 0
Sironax (Beijing) CO., Ltd
8-10/F, Building 2,
Medical Technology Center,
Zhongguancun Life Science Park,
Changping District, Beijing, China
102206
Country 115180 0
China
Phone 115180 0
+86 18758151622
Fax 115180 0
Email 115180 0
Weiliang.fan@sironax.com

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


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.