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Trial registered on ANZCTR


Registration number
ACTRN12621000576820
Ethics application status
Approved
Date submitted
25/02/2021
Date registered
17/05/2021
Date last updated
24/01/2022
Date data sharing statement initially provided
17/05/2021
Date results information initially provided
24/01/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
To Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZ-3102 (single and multiple ascending doses) in Healthy Volunteers
Scientific title
A First-in-Human, Randomized, Double-Blind, Placebo-Controlled, Sequential-Panel, Ascending Single- and Multiple-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZ-3102 in Healthy Volunteers
Secondary ID [1] 303259 0
AZA-001-31-01
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Lysosomal storage disorders 320453 0
Condition category
Condition code
Human Genetics and Inherited Disorders 318346 318346 0 0
Other human genetics and inherited disorders
Metabolic and Endocrine 319541 319541 0 0
Other metabolic disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
"Up to 88 healthy men or women will be enrolled in this study. There will be two parts to the study.

In the first part of the study approximately 52 healthy men and women will be enrolled in up to 6 single ascending dose cohorts comprising 8 participants each. Participants within each cohort will be randomised to receive a single dose of either oral AZ-3102 (6 participants) or oral placebo (2 participants). A total of 12 subjects will be enrolled in one of the 6 cohorts (9 randomised to AZ-3102, 3 to placebo) All cohorts will be started with sentinel dosing. The study drug will be administered under direct observation in the Phase 1 unit. The starting doses for the first cohort will be 1 mg. In the following cohorts, dose will be escalated based on plasma pharmacokinetic (PK), safety and tolerability

In the second part of the study approximately 36 healthy men and women will be enrolled into up to 3 multiple ascending dose cohorts comprising 12 participants each. Participants within each cohort will be randomised to receive multiple doses of either oral AZ_3102 (9 participants) or oral placebo (3 participants). Each dose regimen will be administered for 14 days dosing every 24 hours The doses for each cohort will be selected based on available PK, safety and tolerability data from the Single ascending dose (SAD) part and previous Multiple ascending dose (MAD) cohorts"
for SAD component: It is planned that the maximum possible dose will be 40mg AZ3102, however it is yet to be determined.
mode of administration: Oral capsules.
To assess or monitor adherence to the intervention: both checks of the returned bottle and mouth checks are conducted to monitor adherence to the protocol
Intervention code [1] 319568 0
Treatment: Drugs
Comparator / control treatment
Placebo control group. Placebo is a capsule filled with microcrystalline cellulose matched to the AZ-3102 capsule
Control group
Placebo

Outcomes
Primary outcome [1] 326316 0
To assess the safety and tolerability of AZ-3102 when administered as a single oral dose or a 14-day repeat oral dose to healthy volunteers.
Timepoint [1] 326316 0
Treatment-emergent adverse events will be collected from the time of signing the informed consent form through the final follow-up visit which is on Day 8 and Day 22 for the SAD and the MAD part, respectively.
Full Physical Examinations will be performed at Screening and Day 8 follow-up visit (SAD) or Day 22 follow-up visit (MAD). Symptom Directed Physical Examinations will be performed otherwise
Vital Signs will be assessed at Screening and at Day -1, and thereafter
SAD Part
Day 1: Pre-dose, 0.25 h post-dose; 0.5 h post-dose; 1 h post-dose; 2 h post-dose; 4 h post-dose; 6 h post-dose and 12 h post-dose;
Day 2: 24 h post-dose and 36 h post-dose;
Day 3: 48 h post-dose;
Day 4: 72 h post-dose;
Day 5: 96 h post-dose;
Day 8 at Follow up visit;

MAD Part
Day 1: Pre-dose; 2 h post-dose; 6 h post-dose; 12 h post-dose;
Day 2: Pre-dose; 12 h post-dose;
Day 3, Day 4, Day 5, Day 8 and Day 11: Pre-dose;
Day 14: Pre-dose; 2 h post-dose; 4 h post-dose; 6 h post-dose; 12 h post-dose;
Day 15: 24 h post-dose; 36 h post-dose;
Day 16: 48 h post-dose;
Day 17: 72 h post-dose;
Day 22 at Follow up visit;

ECG will be performed at Screening and at Day -1, and thereafter
SAD Part
Day 1: Pre-dose, 0.5 h post-dose; 1 h post-dose; 2 h post-dose; 4 h post-dose; 6 h post-dose and 12 h post-dose;
Day 2: 24 h post-dose;
Day 3: 48 h post-dose;
Day 4: 72 h post-dose;
Day 5: 96 h post-dose;
Day 8 at Follow up visit;

MAD Part
Day 1: Pre-dose; 2 h post-dose; 6 h post-dose; 12 h post-dose;
Day 2, Day 3, Day 4, Day 5, Day 8 and Day 11: Pre-dose;
Day 14: Pre-dose; 2 h post-dose; 6 h post-dose; 12 h post-dose;
Day 15: 24 h post-dose;
Day 16: 48 h post-dose;
Day 17: 72 h post-dose;
Day 22 at Follow up visit;

Safety Laboratory testing for blood chemistry, hematology, coagulation and urinalysis will be done at Screening and at Day -1, and thereafter
SAD Part
Day 2: 24 h post-dose;
Day 4: 72 h post-dose;
Day 8 at Follow up visit;

MAD Part
Day 2 and Day 8: Pre-dose;
Day 17: 72 h post-dose;
Day 8 at Follow up visit;
Primary outcome [2] 326317 0
To investigate the plasma and urine pharmacokinetic (PK) characteristics of AZ-3102 after single ascending oral doses (SAD) or multiple ascending doses (MAD) of AZ-3102 in healthy subjects.
AUC, Cmax, Tmax
Timepoint [2] 326317 0
SAD Part
Blood PK Sampling: Pre-dose and 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, 72, and 96 hours post-dose following the single dose administration.
Urine PK Sampling: Pre-dose and 0 to 6, 6 to 12, 12 to 24, 24 to 48, 48 to 72 hours and 72 to 96 hours post-dose following the dose administration.

MAD Part
Blood PK Sampling:
Study Day 1: Pre-dose then 1, 2, 4, 6, 12, and 24 hours at trough post-dose
Study Day 2: Pre-dose and 12, 24 hours at trough post-dose.
Study Days 3, 4, 5, 8 and 11: Pre-dose only
Study Day 14: Pre-dose and 1, 2, 4, 6, 12, 24, 36, 48 and 72 hours post-dose
Urine PK Sampling
Study Day 1 Pre-dose and 0 to 6, 6 to 12, 12 to
24 hours post-dose following the first dose administration
Study Days 2 to 4: 0 to 24 hours post-dose following the dose administration in the respective day
Study Day 14: Pre-dose and 0 to 6, 6 to 12, 12 to 24, 24 to 48, and 48 to 72 hours post-dose following the Day 14 dose administration
Secondary outcome [1] 391032 0
To investigate the pharmacodynamic (PD) response to AZ-3102 in healthy subjects in plasma and in the CSF.
Timepoint [1] 391032 0
PD parameter: plasma and CSF concentration of -Ceramide, Glucosylceramide, Lactosylceramide and GM3 (Monosialodihexosylganglioside)
Plasma PD Sampling SAD Part
Day 1: Pre-dose, 2 h post-dose; 6 h post-dose and 12 h post-dose;
Day 2: 24 h post-dose and 36 h post-dose;
Day 3: 48 h post-dose;
Day 4: 72 h post-dose;

MAD Part
Day 1: Pre-dose; 2 h post-dose; 6 h post-dose; 12 h post-dose;
Day 2: Pre-dose; 12 h post-dose;
Day 3, Day 5, and Day 11: Pre-dose;
Day 14: Pre-dose; 2 h post-dose; 6 h post-dose; 12 h post-dose;

PD sampling
Pre-dose Day -1 and thereafter
SAD Part
Day 1: 6 h post-dose or 12 h post-dose;
Day 2: 24 h post-dose
MAD Part
Day 1: 6 h post-dose or 12 h post-dose;
Day 2: Pre-dose
Day 14: 6 h post-dose or 12 h post-dose;
Day 15: 24 h post-dose;
Day 15: 24 h post-dose; 36 h post-dose;
Day 16: 48 h post-dose;
Day 17: 72 h post-dose;
Secondary outcome [2] 392152 0
To investigate the CSF pharmacokinetic (PK) characteristics of AZ-3102 after a single oral dose at one dose level and after the first dose, and the last dose of multiple oral doses in healthy subjects. CSF sampling for PK analysis will be undertaken at the same time of the PD sampling.
Timepoint [2] 392152 0
Dose proportionality will be assessed following study drug administration i.e once in the morning of Day 1 to Day 14

Mean changes of drug concentration in the CSF from pre-dose and will be assessed following study drug administration i.e once in the morning of Day 1 to Day 14

MAD: At Day -1 pre-dose and then at 6-, 12-, or 24-hours post-dose following the dose administration in the respective day on Day 1 and Day 14
Secondary outcome [3] 394970 0
To investigate the Urinary excretion of AZ-3102 following single oral administration of AZ-3102
Timepoint [3] 394970 0
• Ae(0-t) (amount of AZ-3102 excreted in urine from time zero to time t = 6h, 12h, 24h, 48h, 72h and 96h expressed as mg and percent of dose excreted).

Eligibility
Key inclusion criteria
1. Subjects must be able and willing to give written informed consent and are willing to comply with the requirements and restrictions of the study.
2. Subject must be at least 18 years of age at Screening and maximum 55 years of age on date of first dose.
3. A male participant with a female partner of childbearing potential is eligible if he agrees to follow the contraceptive guidance.
4. Female subject is eligible if she is not a woman of childbearing potential (WOCBP) OR, if she is a WOCBP, she agrees to follow the contraceptive guidance.
5. Body mass index (BMI) of greater than or equal to 18.0 kg/m2 and less than or equal to 30.0 kg/m2 at Screening.
6. Healthy as determined by the Investigator, based upon a medical evaluation including medical history, physical examination, clinical laboratory tests, and 12-lead ECG performed at Screening. Out of range values can be repeated once.
7. Subjects must be willing to use adequate contraception, and to refrain from sperm donation, from the time of dosing until 90 days after the last dose of study drug.
8. Subjects that undergo CSF collection: subjects must be willing and able to undergo CSF collections using a lumbar puncture.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Subjects will be excluded if they meet any of the following criteria:
1. Prior or ongoing medical condition, medical history, physical findings, ECG findings, laboratory, or vital signs abnormality that, in the Investigator’s opinion, could adversely affect the safety of the subject.
2. History of clinically significant drug allergies.
3. Alkaline phosphatase, aspartate aminotransferase (AST), and/or alanine aminotransferase (ALT) level greater than 1.5 x upper limit of normal (ULN) at Screening.
4. Creatinine clearance less than 90 mL/min (according to Cockcroft-Gault formula).
5. Total bilirubin greater than 1.5 x ULN (isolated bilirubin greater than 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin is less than 35%).
6. Platelet count less than 100 x 10^9/L
7. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 21 days or five half-lives (whichever is longer) before the first dose of study drug, unless in the opinion of the Investigator and Sponsor’s Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
8. ECG with an average of triplicate QTcF interval greater than 450 msec.
9. A female subject who has a positive pregnancy test at screening or Day -1, or is breastfeeding.
10. Positive urine drug screen or positive alcohol breath test at Screening or Day -1.
11. History of alcohol abuse within 6 months prior to Screening, defined as an average weekly intake of greater than 10 units.
12. Positive urine cotinine at screening or Day -1.
13. Positive result at screening for any of the following infectious disease tests: hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab), human immunodeficiency virus antigen and antibody (HIV Ag, HIV Ab)
14. History of seizure, head trauma, loss of consciousness, symptomatic orthostatic hypotension (e.g. postural syncope).
15. Donation of 500 mL or more blood within 3 months prior to the first dose of study drug; or any amount of plasma in the 7 days prior to Screening; or any amount of platelets in the 42 days prior to Screening.
16. Receipt of an investigational product within 90 days prior to the first dose of study drug or exposure to more than four new chemical entities within 12 months prior to the first dose of study drug.
17. CSF subjects: Any condition or anatomic abnormality that would preclude spinal CSF collection by lumbar puncture or contraindications to lumbar puncture such as papilledema/raised intracranial pressure, infection near lumbar puncture site.
18. Evidence of suicidal ideation with intent (Type 4-5) on the Columbia Suicide Severity Rating Scale (C-SSRS) at Screening (Part 2 MAD only).
19. Attempted suicide attempt in the 6 months before Screening.
20. Employee or immediate family member (eg, spouse, parent, child, sibling) of clinical research unit (CRU) or of the Sponsor.

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)
RAH Pharmacy issues HDPE containers clearly labelled according GMP and local regulations including the participant’s randomisation number. IP or placebo is concealed/ blinded, Clinic Staff and participant will only receive a container which conceals the treatment being administered. One or more container(s) is/are issued per participant per day depending on the dose level and Part of the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomization using a randomization table created by computer software (i.e. computerised sequence generation), creating randomization schedule using SAS.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
23/03/2021
Date of last participant enrolment
Anticipated
2/09/2021
Actual
24/09/2021
Date of last data collection
Anticipated
20/10/2021
Actual
13/10/2021
Sample size
Target
88
Accrual to date
Final
35
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 18751 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 33195 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 307668 0
Commercial sector/Industry
Name [1] 307668 0
Azafaros
Country [1] 307668 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Azafaros
Address
Azafaros, Level 1, 1805 Gold Coast Highway, Burleigh Heads, Queensland 4220, Australia
Country
Australia
Secondary sponsor category [1] 308365 0
None
Name [1] 308365 0
Address [1] 308365 0
Country [1] 308365 0
Other collaborator category [1] 281624 0
Commercial sector/Industry
Name [1] 281624 0
Novotech (Australia) Pty Limited
Address [1] 281624 0
Novotech (Australia) Pty Limited
Level 3, 235 Pyrmont Street, Pyrmont NSW 2009, Australia
Country [1] 281624 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307707 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 307707 0
123 Glen Osmond Road, Eastwood SA 5063, Australia
Ethics committee country [1] 307707 0
Australia
Date submitted for ethics approval [1] 307707 0
13/01/2021
Approval date [1] 307707 0
16/02/2021
Ethics approval number [1] 307707 0
2021-01-016

Summary
Brief summary
This study is a prospective, randomized, double-blind, placebo controlled, two-part, Phase 1 clinical study to evaluate the safety, tolerability, PK and PD of oral single-ascending doses (SAD) and oral multiple-ascending doses (MAD) of AZ-3102 in healthy female and male subjects (between 18 and 55 years of age, inclusive), with body mass index between 18 and 30 kg/m^2.
The study consists of 2 parts: SAD and MAD.
A total of 88 healthy subjects are planned for the study:
Part 1 (SAD): 52 subjects (6 cohorts); Part 2 (MAD): 36 subjects (3 cohorts). In the MAD part all subjects will receive once daily dosing of AZ-3102 over 14 days.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 108214 0
Dr Thomas Polasek
Address 108214 0
CMAX Clinical Research Pty Ltd, Level 5, 18a North Terrace, Adelaide, South Australia 5000, Australia
Country 108214 0
Australia
Phone 108214 0
+61 8 7088 7939
Fax 108214 0
Email 108214 0
[email protected]
Contact person for public queries
Name 108215 0
Ms Katherine Mudge
Address 108215 0
CMAX Clinical Research Pty Ltd, Level 5, 18a North Terrace, Adelaide SA 5000, Australia
Country 108215 0
Australia
Phone 108215 0
+61 8 7088 7900
Fax 108215 0
Email 108215 0
[email protected]
Contact person for scientific queries
Name 108216 0
Dr Ruben Giorgino
Address 108216 0
Azafaros, Level 1, 1805 Gold Coast Highway, Burleigh Heads, Queensland 4220
Country 108216 0
Australia
Phone 108216 0
+41 79 533 77 44
Fax 108216 0
Email 108216 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


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
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