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Trial registered on ANZCTR


Registration number
ACTRN12621000400864
Ethics application status
Approved
Date submitted
10/02/2021
Date registered
9/04/2021
Date last updated
23/12/2021
Date data sharing statement initially provided
9/04/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
A randomized, open-label and two-way crossover study to evaluate the effects of SIR1-365 after a single oral dose of 300 mg on the activities of CYP450 isoform 3A in healthy young subjects
Scientific title
A randomized, open-label and two-way crossover study to evaluate the effects of SIR1-365 after a single oral dose of 300 mg on the activities of CYP450 isoform 3A in healthy young subjects
Secondary ID [1] 303324 0
SIR365-AU-103
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neurodegenerative disease 320593 0
inflammatory disease 320594 0
Condition category
Condition code
Inflammatory and Immune System 318413 318413 0 0
Other inflammatory or immune system disorders
Neurological 318415 318415 0 0
Neurodegenerative diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
SIR1-365 is a potent and selective allosteric kinase inhibitor of RIP1 with favorable drug-like properties in vitro and in vivo. RIP1 inhibitors may be beneficial for the treatments of degenerative diseases including neurodegenerative and systemic inflammatory diseases. However, no RIP1 inhibitors have been assessed yet in large clinical studies for any of those diseases. In vitro work has shown weak inhibition of SIR1-365 on the activity of CYP450 isoform 3A4. Thus, the objective of this study is to evaluate the effects of SIR1-365 after a single oral dose of 300 mg on the activities of CYP450 isoform 3A by comparing the PK profiles of midazolam (the sensitive index substrate for CYP450 isoform 3A) when administered alone or together with SIR1-365.

This will be a randomized, open-label, single-dose and two-way crossover study to assess effects of SIR1-365 after a single oral dose of 300 mg on the activities of CYP450 isoform 3A in healthy young subjects using sensitive index substrates (midazolam) for CYP450 isoform 3A. The total duration of participation for each subject will be up to 41 days including up to 27 days for screening, 7 days in the unit and a follow-up phone call about 7 days after discharge from the unit. Approximately 10 male and 10 female healthy subjects will be randomized to the study according to a randomization schedule prepared before the start of the study.

After an overnight fast for at least 10 hours, subjects in Sequence 1 will receive a single dose of midazolam oral solution at 5 mg alone (prepared from Midazolam injection ampoule 5mg/mL), while subjects in Sequence 2 will receive a single oral 300mg dose of SIR1-365 tablets plus a single dose of midazolam oral solution at 5 mg. Both treatments will be administered under fasted conditions and study staff will instruct subjects to take the study medication exactly as instructed as compliance is necessary for subject safety and for the validity of the study. After a wash-out period of 4 days after the first dose, subjects will receive the alternate treatment.
Intervention code [1] 319634 0
Treatment: Drugs
Comparator / control treatment
After an overnight fasting for at least 10 hours, subjects in Sequence 1 will receive a single oral dose of midazolam at 5 mg alone (prepared from Midazolam injection ampoule 5 mg/mL).
Control group
Active

Outcomes
Primary outcome [1] 326400 0
To obtain the pharmacokinetic profile of midazolam and it’s metabolite 1-hydroxymidazolam, when midazolam is administered with SIR1-365. Pharmacokinetic parameters of AUC and Cmax will be calculated.
Timepoint [1] 326400 0
Fourteen blood samples will be collected at the following timepoints; 30 min before dosing, and 0.25 hour, 0.5 hour, 1 hour (+/-2 min), 1.5 hour, 2 hours, 3 hours, 4 hours (+/- 5 min), 16 hours and 24 hours after dosing.
Primary outcome [2] 326814 0
To obtain the pharmacokinetic profile of midazolam and it’s metabolite 1-hydroxymidazolam, when midazolam is administered alone. Pharmacokinetic parameters of AUC and Cmax will be calculated.
Timepoint [2] 326814 0
Fourteen blood samples will be collected at the following timepoints; 30 min before dosing, and 0.25 hour, 0.5 hour, 1 hour (+/-2 min), 1.5 hour, 2 hours, 3 hours, 4 hours (+/- 5 min), 16 hours and 24 hours after dosing.
Secondary outcome [1] 391325 0
Safety will be continuously monitored using composite of data available through physical exam and laboratory assessments.

Clinical Laboratory tests include:
- Blood haematology
- Blood chemistry
- Blood coagulation
- Urinalysis

A complete physical examination will include but not limited to the evaluation of the following organs or body systems: skin; head, eyes, ears, nose, and throat; thyroid; respiratory, cardiovascular, and central nervous systems; abdomen (liver and spleen); lymph nodes; and extremities.
Timepoint [1] 391325 0
Days 1, 2, 3, 4 , 5, 6 and 13 after intervention. A complete physical examination will be completed at day 6. Complete Vital Signs Measurements will be completed pre-dose and 24 hours post dose (First dose administered on Days 1 & 5). Oxygen saturation will be measured (pulse oximetry) every 15 minutes up to 1 hour following administration of midazolam. 12-lead Electrocardiogram (ECG) and Clinical Laboratory tests will be completed at Day 6. Adverse Events will be monitored at all visits.

Eligibility
Key inclusion criteria
1. Are capable of signing informed consent form (ICF) and complying with study procedures;
2. Male or female healthy subjects between the ages of 18 and 45 years old, inclusive;
3. Women of childbearing potential (WOCBP) must have a negative pregnancy test at Screening and 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 > 1 year postmenopausal or surgically sterile (ie, hysterectomy, bilateral oophorectomy, or bilateral salpingectomy tubal ligation). If serum ßHCG is the standard of care, then this value can be used to determine eligibility. 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), during and for 90 days after participation in the study.
4. Considered healthy by the Principal Investigator (PI), based on a detailed medical history, full physical examination, clinical laboratory tests, 12-lead ECG and vital signs;
5. Nonsmoker, defined as not having smoked more than 2 cigarettes a day during the 6 months before screening.;
6. Able to abstain from the consumption of alcohol and any alcohol-containing products from 48 hours before dosing through the end of the in house confinement;
7. Able to limit the consumption of coffee and any caffeine-containing products to four cups a day during the study;
8. Body mass index (BMI) of (>18 but <30 kg/m2 inclusive and body weight not less than 50 kg;
9. Willing and able to adhere to study restrictions and to be confined at the clinical research center.
Minimum age
18 Years
Maximum age
45 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, alkaline phosphatase greater than or equal to 2 times upper limit of normal (ULN), total bilirubin greater than or equal to 2.0 times ULN, or albumin less than or equal to 3 g/dL at screening;
4. Abnormal findings indicating renal impairment, such as positive urine protein (defined as greater than or equal to 1+ on repeated testing), creatinine greater than or equal to 1.5 times ULN, at screening;
5. Clinically significant ECG findings such as QTc value greater than or equal to 450 ms for male or 470 ms for female at screening;
6. Subjects with a mean systolic blood pressure of three measurements >150 mmHg, or a mean diastolic blood pressure of three measurements >90 mmHg at screening. Blood pressure will be measured at sitting position;
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;
9. A history of seizure. However, a history of febrile seizure is allowed;
10. Positive pregnancy test result at screening and baseline, or plan to become pregnant within 30 days after the end-of-study if female;
11. A hospital admission or major surgery within 60 days prior to screening;
12. Participation in any other investigational drug trial within 30 days prior to screening;
13. DSM-V substance use disorders within 6 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;
15. An unwillingness or inability to comply with food and beverage restrictions during study participation;
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 over-the-counter medications (except paracetamol up to 24 hours prior to dosing), and herbal medicines (including St John’s Wort, herbal teas, garlic extracts) within 30 days prior to dosing;
18. A history of suicide attempt in the past 12 months and/or seen by the investigator as having a significant risk of suicide or homicide;
19. An unwillingness of male participants to use appropriate contraceptive measures if engaging in sex intercourse with a female partner of childbearing potential during the study and up to 30 days after discontinuation of study treatment. Sexual intercourse with pregnant or lactating women is prohibited.
20. Subject has a known or suspected hypersensitivity to benzodiazepines, SIR1-365 and any components of SIR1-365 tablets.

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 manual randomisation scheme (central randomisation - computer), developed prior to the initiation of the study. This is separate from the enrolment process.
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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
A detailed statistical analysis plan (SAP) will be developed and finalized before database lock.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
26/03/2021
Date of last participant enrolment
Anticipated
Actual
8/04/2021
Date of last data collection
Anticipated
20/04/2021
Actual
19/04/2021
Sample size
Target
20
Accrual to date
Final
20
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 18566 0
Scientia Clinical Research - Randwick
Recruitment postcode(s) [1] 32939 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 307741 0
Commercial sector/Industry
Name [1] 307741 0
Sironax Australia Pty Ltd
Country [1] 307741 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Sironax Australia Pty Ltd
Address
Level 40, 2-26 Park Street, Sydney, NSW 2000
Country
Australia
Secondary sponsor category [1] 308443 0
None
Name [1] 308443 0
Address [1] 308443 0
Country [1] 308443 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307767 0
Bellberry Ltd
Ethics committee address [1] 307767 0
Ethics committee country [1] 307767 0
Australia
Date submitted for ethics approval [1] 307767 0
03/02/2021
Approval date [1] 307767 0
17/03/2021
Ethics approval number [1] 307767 0
HREC2021-02-089

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

Contacts
Principal investigator
Name 108422 0
Dr Dr Christopher Argent
Address 108422 0
Scientia Clinical Research Ltd
Bright Building, Level 5, Corner of High & Avoca Street, Randwick, Sydney NSW 2031
Country 108422 0
Australia
Phone 108422 0
+61 2 9382 5800
Fax 108422 0
Email 108422 0
christopher.argent@scientiaclinicalresearch.com.au
Contact person for public queries
Name 108423 0
Michelle Glasel
Address 108423 0
Scientia Clinical Research Ltd
Bright Building, Level 5, Corner of High & Avoca Street, Randwick, Sydney NSW 2031
Country 108423 0
Australia
Phone 108423 0
+61 2 9382 5831
Fax 108423 0
Email 108423 0
michelle.glasel@scientiaclinicalresearch.com.au
Contact person for scientific queries
Name 108424 0
Michelle Glasel
Address 108424 0
Scientia Clinical Research Ltd
Bright Building, Level 5, Corner of High & Avoca Street, Randwick, Sydney NSW 2031
Country 108424 0
Australia
Phone 108424 0
+61 2 9382 5831
Fax 108424 0
Email 108424 0
michelle.glasel@scientiaclinicalresearch.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
Combined de-identified participant data may be made publicly available through peer reviewed journal publications or presentations at professional forums.


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.