Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000375651
Ethics application status
Approved
Date submitted
28/03/2023
Date registered
13/04/2023
Date last updated
17/09/2023
Date data sharing statement initially provided
13/04/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Part 1 and Part 3:A Study to evaluate the safety,Tolerability,Pharmacokinetics of AC-201
Scientific title
A Single Center,Randomized,Double-blind,Placebo-controlled,Sequential Parallel Group,Single and Multiple Ascending Dose Study Following Oral Administration in Healthy Subjects to Evaluate the Safety,Tolerability,Pharmacokinetics of AC-201 (Parts 1 and 3)
Secondary ID [1] 309306 0
AC-201-AU-PhIa
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Psoriasis 329502 0
Condition category
Condition code
Skin 326437 326437 0 0
Dermatological conditions

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Accro Bioscience is developing AC-201, a potent and selective oral small molecule inhibitor of tyrosine kinase 2 (TYK2) and JAK1, indicated for treatment of the moderate-to-severe plaque psoriasis.
Dosage Form:Tablet
Mode of Administration:Oral
For Part 1 (Single Ascending Dose):
A total of 40 subjects in 5 dose levels including 5mg,15mg,50mg,100mg and 200mg will be evaluated.Subjects will take investigational drug or placebo under fasted condition.
For each cohort, subjects will be admitted to the clinical research unit(CRU) on Day -1 before dosing (Day 1) and remain sequestered at the CRU until Day 4
Cohort1:5mg AC-201 single oral administration on Day1
Cohort2:15mg AC-201 single oral administration on Day1
Cohort3:50mg AC-201 single oral administration on Day1
Cohort4:100mg AC-201 single oral administration on Day1
Cohort5:200mg AC-201 single oral administration on Day1
lmmediately after dose administration, visual,inspection of the mouth and hands will be performed for each subject.

Part 3 (Multiple Ascending Dose):
AC-201 dosing regimens (dose levels and duration of administration) will be modified based on the collective SAD PK and safety data from Part 1 and Part 2. SRC meeting to review safety data prior to dose escalation to subsequent cohort.
A total 30 subjects(these participants will be unique to the participants enrolled in Part 1),in 3 dose levels including 5mg(once daily), 15mg(twice daily) and 50mg(once daily) will be evaluated;
Subjects will take investigational drug or placebo under fasted condition and will have a total of 16 overnight stays
Cohort1:5mg AC-201 once daily for consecutive oral 14 days i.eDay1 to Day 14;
Cohort2:15mg AC-201 twice daily for consecutive oral 14 days i.eDay1 to Day 14;
Cohort3:50mg AC-201 once daily for consecutive oral 14 days i.eDay1 to Day 14;
(10 subjects in each dose cohort for a total of 3 cohorts,8subjects randomized to active drug and 2 subjects randomized to placebo per cohort). The dosing regimen is for a consecutive 14 days (AC-201/Placebo will be taken orally once in the morning on D14 in the 15 mg bid cohort). Subjects will take investigational drug or placebo under fasted condition and will have a total of 16 overnight stays (admission on Day -1 until Day 16 in the study).
lmmediately after dose administration, visual,inspection of the mouth and hands will be performed for each subject.

All doses of study drug will be administered orally with approximately 240 mL of room temperature water. Water consumption will be restricted from 1h prior to dosing until 2h after dosing, when water will be available to maintain adequate hydration. For some participants, they may require extra water. Providing additional water eg. 100 mL to be allowed and documented to assist with dose administration if required.

ln part 1 and part 3 the participants are dosed at the site, they will receive study treatment directly from the Investigator or designee, under medical supervision. lmmediately after dose administration, visual,inspection of the mouth and hands will be performed for each subject. The date and time of each dose administered will be recorded in the source documents. The dose of study treatment and study participant identification will be confirmed at the time of dosing by a member of the study site staff other than the person administering the study treatment.
Intervention code [1] 325748 0
Treatment: Drugs
Comparator / control treatment
The placebo tablets will be identical in appearance to the AC-201 and will be adiministered orally.
Placebo to match consists of microcrystalline cellulose, lactose monohydrate, and magnesium stearate.
Control group
Placebo

Outcomes
Primary outcome [1] 334284 0
in accordance with the Common Terminology Criteria for Adverse Events (CTCAE5.0) to evaluate the safety and tolerability of AC-201 following oral dose administration assessed by.
- lncidence and severity of adverse events (AE);(The reversible decreased mean erythrocyte count (RBC), hemoglobin (HGB) and hematocrit (HCT) values accompanying decreased reticulocyte count (#RET)were noted in rats and dogs studies).
- Clinically significant changes from baseline in laboratory evaluations(hematology, blood biochemistry, urine routine and coagulation function). The blood sample and urine sample need collected from participants for laboratory evaluations;
-12-lead Electrocardiograms (12-lead ECGs)
- Vital signs(include blood pressure, pulse rate, respiratory rate, tympanic temperature.)
Blood pressure assessed using a sphygmomanometer
Pulse rate and Resp rate is measured manually by the medical staff using clock. Temperature is measured using tympanic thermometer.
- Physical examinations(General Appearance, HEENT(Head, Eyes, Ears, Nose, and Throat), Mouth/Dental, Neck (include Thyroid & Nodes), Cardiovascular, Respiratory, Gastrointestinal, Renal, Neurological, Musculoskeletal, Skin,)
Timepoint [1] 334284 0
Adverse Events:
Part 1 SAD - Daily from Screening to Day 4 post-dose
Part 3 MAD - Daily from Screening to Day 16 post-first dose

Clinical Laboratory tests (hematology, chemistry, coagulation, and urinalysis)
Part 1 SAD;
-Screening
- Day -1(pre-dose)
- Day 2 post-dose
- Day 4 post-dose
Part 3 MAD;
- Screening
- Day -1 (pre-first dose)
- Day 2 post-first dose
- Day 5 post-first dose
- Day 8 post-first dose
- Day 12 post-first dose
- Day 16 post-first dose

12-lead ECGs:
Part 1 SAD - Screening.on D-1, pre-dose (within 1h prior to dosing) and at 30min, 1h, 2h, 24h, 48h post-dose and D4
Part 3 MAD - Screening,on D-1, and on D1 pre-dose (within 1h prior to dosing) and at 30±10min,1h±10min, 2h±30min post-dose; and at 30±10min post-dose on D2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13; and D14 pre-dose (within 1h prior to dosing) and at 30min,1h, 2h, 24h, 48h post-dose

Vital Signs:
Part 1 SAD - Screening, on D-1, D1 pre-dose (within 1h prior to dosing) and at 30min,1h, 2h, 24hn, 48h post-dose.
Part 3 MAD -Screening, on D-1, and on D1 pre-dose (within 1h prior to dosing) and at 30min,1h, 2h post-dose; and at 30min post-dose on D2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13; and on D14 pre-dose (within 1h prior to dosing) and at 30min,1h, 2h, 24h, 48h post-dose.

Physical Examination:
Part 1 SAD - Screening, on D4 or early termination,
Part 3 MAD -Screening, on D16 or early termination
Secondary outcome [1] 420124 0
• To characterize the pharmacokinetics of AC-201 following oral single/multiple dose administration;
The drug concentrations of AC-201 in plasma; the main pharmacokinetic parameters: Cmax, Tmax, t1/2, AUClast, and AUCinf, MRT, CL/F, Vz/F, kel, Cmin,ss, Cmax,ss, Cav,ss, AUC0-t, steady-state fluctuation coefficient (DF), and accumulation ratio (rac)
Timepoint [1] 420124 0
Party 1 SAD
PK: D1 pre-dose (within 1h prior to dosing) and at 15min,30min, 1h,1.5h, 2h, 4h, 6h, 8h, 12h, 24h and 48h post-dose.
Biomarker/PD: D1 pre-dose (within 1h prior to dosing) and at 1.5h, 8h and 24h post-dose.

Party 3 MAD
PK:The 15mg twice daily cohort:
- Day 1: pre-morning dose (within 1h prior to morning dosing) and at 15min, 30min, 1, 1.5, 2,4,6,8,12, 12.5, 13, 13.5, 14, and 24hrs post-Day 1 morning dose;
-Day 3-7, Day 10 and Day 13 post-first dose: pre-dose (within 1 h prior to first dosing);
- Day 14 post-first dose: pre-dose (within 1h prior to dosing) and at 15min, 30min, 1, 1.5, 2, 4, 6, 8, 12, 24 and 48hrs post-dose.

PK:The 15mg once daily and 50mg once daily cohorts:
- Day 1: pre-dose (within 1h prior to dosing) and at 15min, 30min, 1, 1.5, 2, 4, 6, 8, 12 and 24hrs post-dose and 48hrs post-dose from D14;
- Day 3-7, Day 10 and Day 13 post-first dose: pre-dose (within 1h prior to dosing)
- Day 14 post-first dose: pre-dose (within 1h prior to dosing) and at 15min, 30min, 1, 1.5, 2, 4, 6, 8, 12, 24 and 48hrs post-dose.

Eligibility
Key inclusion criteria
1. Are capable of giving informed consent and complying with study procedures;
2. Are between the ages of 18 and 60 years, inclusive;
3. Body mass index (BMI) of 18.0 to 32.0 kg/m2 inclusive and body weight not less than 50 kg for male and 45 kg for female, and no more than 120 kg;
4. Female subjects have a negative serum pregnancy test result at screening and a negative urine pregnancy test result Day -1, and meet one of the following criteria:
• Using highly effective method of contraception such as implants, injectables, oral contraceptives, intrauterine devices (IUDs), intrauterine hormone-releasing system (IUS) at least 3 months prior to screening and willing to continue the control for the duration of the study and until 1 month after dosing with the study drug.
• Surgically sterile for at least 3 months prior to screening by one of the following means:
• Bilateral salpingectomy (with or without oophorectomy)
• Surgical hysterectomy
• Vasectomized partner
• Bilateral oophorectomy (with or without hysterectomy)
• Postmenopausal, defined as the following:
• Last menstrual period greater than 12 months prior to screening
• Postmenopausal status confirmed by serum follicle stimulating hormone (FSH) level is
greater than or equal to 30 IU/L at screening;
5. Male subjects with female partners of child bearing potential must agree to use condoms and use highly effective method of contraception with female partner for the duration of the study and until 3 months after dosing with the study drug;
6. Subjects who are exclusively in same-sex relationships and abstain completely for the duration of study and 3 months after the last study treatment are exempt from the contraceptive requirements;
7. Considered healthy by the Investigator, based on subject’s reported medical history, full physical examination, clinical laboratory tests, 12-lead ECG, and vital signs;
8. Willing and able to adhere to study restrictions and to be confined at the clinical research center.
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Evidence of clinically significant hematologic, renal, endocrine, pulmonary, cardiac, gastrointestinal (GI), hepatic, psychiatric, neurologic, immunologic, Gilbert’s Syndrome and allergic disease (including multiple clinically significant drug allergies or food intolerances; mild and inactive hayfever is permitted), or any other condition, in the opinion of the Investigator, might significantly interfere with the absorption, distribution, metabolism, or excretion of study drug; or place the subject at an unacceptable risk as a participant in this study; resolved childhood asthma, non-hospitalised depression and migraines are not exclusionary unless deemed clinically significant by the investigator;
2. Has had an acute illness considered clinically significant by the Investigator within 30 days prior to screening, minor colds are permitted;
3. Laboratory results (serum chemistry, hematology, coagulation, and urinalysis) outside the normal range at screening and Check-in and considered clinically significant in the opinion of the Investigator. Subjects must be excluded who meet the following laboratory values at the screening visit: Hb<115g/L (Female) and HB<125g/L (Male); Serum creatinine>1.5xULN; Aspartate aminotransferase >1.5xULN; Alanine aminotransferase >1.5xULN; Total bilirubin>1.5xULN; Triglycerides >2mmol/L. One retest of an exclusionary laboratory result is allowed at the discretion of the Investigator;
4. Taken any drug that inhibits or induces liver drug-metabolizing enzymes 30 days prior to screening; Excessive consumption of xanthine-rich diets (including chocolate, tea, coffee, cola, etc.) or other effects that affect the absorption, distribution, metabolism, excretion and other factors of the drug 2 days prior to study drug administration;
5. Clinically significant history with sequelae of gastrointestinal tract, liver, kidney, or other diseases known to interfere drug absorption, distribution, metabolism or excretion (appendicectomy allowed if uncomplicated, hernia surgery allowed if small and no bowel resection, cholecystectomy excluded, bariatric surgery including gastric banding excluded);
6. Prolongation of QTcF (>450 msec for males and >470 msec for females) at screening;
7. eGFR <80mL/min calculated using Cockroft & Gault formula;
8. Cancer or history of lymphoproliferative disease within last 5 years; exception is resected cutaneous basal cell or squamous cell carcinoma that has been treated without recurrence;
9. Positive blood screen for hepatitis C antibody, hepatitis B surface antigen or human immunodeficiency virus (HIV) antibody;
10. A hospital admission or major surgery within 90 days prior to screening;
11. A history of prescription drug abuse, or illicit drug use within 3 months prior to screening;
12. A history of alcohol abuse according to medical history (drinking 4 or more standard drinks (a standard drink equals 10 g of pure alcohol) on any day for women and drinking 5 or more standard drinks on any day for men) within 3 months prior to screening;
13. Has more than 10 cigarettes/week within 30 days prior to screening or intends to use any product containing nicotine during the course of the study;
14. A positive screen for alcohol, and/or drugs of abuse at screening or Day -1; A positive screen for cotinine on Day -1; A repeat is allowed at investigator discretion for suspected false positive;
15. Unwilling to refrain from ingestion of dragon fruit, mango, grapefruit, grapefruit juice, pomelo, star fruit, Seville oranges, Seville orange marmalade or other products containing grapefruit, pomelo, star fruit or Seville oranges or red wine from 7 days prior to study drug administration to the end of the study;
16. Has had any immunizations in the 2 weeks prior to screening;
17. Has used medications that affect GI motility or gastric emptying within 30 days prior to Day 1; or the participants with clinically significant abnormal bowel habits by the Investigator’s opinion, including symptoms of cramping, abdominal pain, bloating, gas, diarrhea and/or constipation;
18. Has used any prescription or over-the-counter medication (with exception of acetaminophen at < 2 g/day is permitted until 48 hours prior to dosing), vitamins/herbal supplements (with the exception of hormonal contraceptives) within 7 days or 5 half-lives of the drug (whichever is longer) prior to Day 1;
19. Poor venous access;
20. Has lost or donated >450 mL of whole blood or blood products within 30 days prior to screening;
21. Taken any investigational drug within 30 days or 5 half-lives whichever is longer;
22. Female who are pregnant or breastfeeding; Positive pregnancy test result;
23. Intending to donate sperm or ova during the study and three months after the end of treatment;
24. Any condition or finding that in the Investigators’ opinion would put the subject or study conduct at risk if the subject were to participate in the study.

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)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
5/06/2023
Actual
26/06/2023
Date of last participant enrolment
Anticipated
23/10/2023
Actual
Date of last data collection
Anticipated
30/11/2023
Actual
Sample size
Target
82
Accrual to date
8
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 24365 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 39949 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 313499 0
Commercial sector/Industry
Name [1] 313499 0
Accro Bioscience (Australia) Pty Ltd
Country [1] 313499 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Accro Bioscience (Australia) Pty Ltd
Address
Level 7, 330 Collins Street, Melbourne Victoria 3000
Country
Australia
Secondary sponsor category [1] 315274 0
None
Name [1] 315274 0
Address [1] 315274 0
Country [1] 315274 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312688 0
Bellberry Human Research Ethics Committee A'
Ethics committee address [1] 312688 0
Bellberry Limited 123 Glen Osmond Road, Eastwood South Australia 5063
Ethics committee country [1] 312688 0
Australia
Date submitted for ethics approval [1] 312688 0
29/03/2023
Approval date [1] 312688 0
15/05/2023
Ethics approval number [1] 312688 0
2023-03-33

Summary
Brief summary
This is a Phase 1, randomized, double-blind, placebo-controlled, first-in-human study in which the safety, tolerability, and PK of orally administered AC-201 will be assessed in healthy adult subjects.
The study will consist of 3 parts: a SAD phase (Part 1) enrolling a total of 5 cohorts of healthy subjects, and a MAD phase (Part 3) enrolling 3 cohorts of healthy subjects.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 125566 0
Dr Alex Choo
Address 125566 0
CMAX Clinical Research Pty Ltd,
Level 5,21North Terrace, Adelaide, South Australia,5000
Country 125566 0
Australia
Phone 125566 0
+61 8 7088 7123
Fax 125566 0
Email 125566 0
Alex.Choo@sa.gov.au
Contact person for public queries
Name 125567 0
Dr Nucleus Network Melbourne
Address 125567 0
Level 5, Burnet Tower,89Commercial Rd, Melbourne 3004, Victoria
Country 125567 0
Australia
Phone 125567 0
+611800243 733
Fax 125567 0
Email 125567 0
melbourne@nucleusnetwork.com
Contact person for scientific queries
Name 125568 0
Mr Xiaohu Zhang
Address 125568 0
Accro Bioscience (Australia) Pty Ltd
Level 7, 330 Collins Street, Melbourne Victoria 3000
Country 125568 0
Australia
Phone 125568 0
+61451332620
Fax 125568 0
Email 125568 0
xiaohu.zhang@accro.com.cn

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.