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Trial registered on ANZCTR


Registration number
ACTRN12620000344998
Ethics application status
Approved
Date submitted
26/02/2020
Date registered
11/03/2020
Date last updated
11/03/2020
Date data sharing statement initially provided
11/03/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A Randomized, Double-blind, Placebo- controlled, Single Ascending Dose (SAD) Study of XW003 Injection in Healthy Adult Participants
Scientific title
A Phase 1, Randomized, Double-blind, Placebo-controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of XW003 (an Investigational Recombinant Human Glucagon-like Peptide-1 Analogue) Injection in Healthy Adult Participants
Secondary ID [1] 300383 0
SCW0502-1011/1012
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 Diabetes Mellitus 316437 0
Nonalcoholic Steatohepatitis 316438 0
Condition category
Condition code
Metabolic and Endocrine 314296 314296 0 0
Diabetes
Metabolic and Endocrine 314297 314297 0 0
Other metabolic disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a first-in-human (FIH), single-centre, double blind, randomised, SAD study of XW003 conducted in healthy adult participants. The study is designed to evaluate the safety, tolerability, PK, and PD of XW003 in healthy participants.
Participants will undergo a Screening period beginning up to 28 days prior to randomisation/dose administration. Participants will undergo pre-dose assessments, post-dose assessments, and will complete an EOS follow-up visit or early termination (ET) visit.
Up to 50 participants will be enrolled into one of up to seven (7) sequential cohorts (Cohorts A1 to A7). Participants in each cohort will be randomised to receive a single subcutaneous (SC) dose of either XW003 or matching placebo on Day 1 following an overnight fast. Two sentinel participants will receive a single SC dose of XW003 initially. If dosing of these sentinel participants proceeds without clinically significant safety signals in the first 48 hours post-dose, the remaining participants will receive a single dose of XW003 or placebo according to the randomisation schedule.

Single SC doses of XW003 will be administered by body weight range. Dose escalation fold will be the same for each body weight range and is planned as follows;
1. Proposed XW003 Dose Levels (50 kg-75 kg): 0.03mg, 0.1mg, 0.2mg, 0.4mg, 0.8mg, 1.2mg and 1.6mg respectively for Cohorts A1 TO A7.
2. Proposed XW003 Dose Levels (76 kg-90 kg): 0.03mg, 0.1mg, 0.25mg, 0.5mg, 1.0 mg, 1.6mg, 2.0mg
These doses are subject to change following SRC review of each cohort – XW003 dose level will not exceed 2.0 mg. Decisions to escalate, expand or decrease the dose will be dependent upon review of emerging safety and PK data by an SRC. The SRC will conduct a review of safety data from each preceding cohort prior to commencement of each proceeding cohort. Details will be provided in an SRC Charter document.
Intervention code [1] 316679 0
Treatment: Drugs
Comparator / control treatment
Volume-matching placebo (solution for injection containing no XW003) will be used and administered by a single SC injection.
Control group
Placebo

Outcomes
Primary outcome [1] 322686 0
To evaluate the safety and tolerability of single ascending doses of XW003 in healthy participants
Timepoint [1] 322686 0
The safety and tolerability of XW003 will be assessed from screening until the End of study or Early Termination(if applicable) visit.
The parameters by which the safety and tolerability of XW003 will be assessed are the incidence, frequency, and severity of treatment-emergent adverse events (TEAEs), including clinically significant vital signs, electrocardiograms (ECGs), hypoglycaemic episodes (including blood glucose monitoring), laboratory test results, injection site reactions (ISRs), and physical examinations.
Secondary outcome [1] 379294 0
To evaluate the pharmacokinetics (PK) of single ascending doses of XW003 in healthy participants
Timepoint [1] 379294 0
XW003 PK Blood samples collection timepoints are as follows:
Day 1 Pre-dose: Within 30 minutes pre-dose,
Day 1 Post Dose: 30 minutes(±10 minutes), 1 hour(±10 minutes), 2 hours(±10 minutes), 4 hours(±10 minutes), 6 hours(±30 minutes), 8 hours(±30 minutes), 9 hours(±30 minutes), 10 hours(±30 minutes), 11 hours(±30 minutes), 12 hours(±30 minutes), 13 hours(±30 minutes), 14 hours(±30 minutes), 16 hours(±1 hour), 18 hours(±1 hour), 20 hours(±1 hour), Day 2 (24 hours ±1 hour), Day 2 (30 hours ±1 hour), Day 2 (36 hours ±1 hour), Day 3 (48 hours ±2 hours), Day 3 (60 hours ±2 hours), Day 4 (72 hours ±4 hours), Day 4 (84 hours ±4 hours), Day 5 (96 hours ±4 hours), Day 5 (108 hours ±4 hours), Day 6 (120 hours ±4 hours), Day 7 (144 hours ±4 hours), Day 8 (168 hours ±4 hours), Day 10 (216 hours ±4 hours), Day 12 (264 hours ±24 hours), Day 15 (336 hours ±48 hours), Day 22 (504 hours ±48 hours)
The parameters by which the pharmacokinetics (PK) of XW003 will be measured are as follows:
• Maximum observed drug concentration (Cmax)
• Time of the maximum drug concentration (Tmax)
• Area under the drug concentration-time curve from time zero to 24 hours post dose (AUC0-24h)
• Area under the drug concentration-time curve from time zero to 48 hours post dose (AUC0-48h)
• Area under the drug concentration-time curve from time zero to 168 hours post dose (AUC0-168h)
• AUC from time zero to infinity (AUC0-inf)
• AUC from time zero to last quantifiable concentration (AUC0-last)
• Apparent terminal half-life (t½)
• Apparent terminal elimination rate constant (Kel)
• Apparent total clearance (CL/F)
• Apparent volume of distribution (VZ/F)
Secondary outcome [2] 379295 0
To evaluate the pharmacodynamics (PD) of single ascending doses of XW003 in healthy participants
Timepoint [2] 379295 0
XW003 PD Blood samples collection timepoints are as follows:
Screening, within 30 minutes prior to dosing on Day 1 and Day 1 (Post Dose): 1 hour(±10 minutes), 2 hours(±10 minutes), 4 hours(±10 minutes), 6 hours(±30 minutes), 8 hours(±30 minutes), 10 hours(±30 minutes), 11 hours(±30 minutes), 12 hours(±30 minutes), and 14 hours(±30 minutes)
The parameters by which the Pharmacodynamics of XW003 will be measured as follows:
• Change from Baseline in body weight
• Change from Baseline in fasting plasma glucose (FPG)
• Change from Baseline in plasma insulin and pro-insulin
• Change from Baseline in plasma C-peptide
• Change from Baseline in plasma glucagon
• Change from Baseline in plasma lipids (triglyceride, low-density lipoprotein [LDL], and high density lipoprotein [HDL])

Eligibility
Key inclusion criteria
To be eligible for this study, a participant has to meet all of the following inclusion criteria:
1. Healthy male or female participants, aged 18 to 55 years (inclusive at the time of informed consent);
2. Participants must be in good general health, with no significant medical history, have no clinically significant abnormalities on physical examination at Screening and/or before administration of study drug;
3. Participants must have a BMI greater than or equal to 20.0 kg/m2 and less than or equal to 35.0 kg/m2 and weigh greater than or equal to 50 kg but less than or equal to 90 kg at Screening;
4. Stable body weight for at least three (3) months prior to Screening (i.e., <5% change);
5. Participants must have A1c below 6.4%, FPG: 3.9 ~ 6.1 mmol/L (both inclusive) or
70~110 mg/dL (both inclusive). All other clinical laboratory values must be within normal range as specified by the testing laboratory, unless deemed not clinically significant by the Investigator or delegate;
6. Non-smoker and/or casual smoker who uses no more than 10 cigarettes (or equivalent quantity of any other nicotine containing products e.g., cigars, chewing tobacco, snuff, etc.) per week. Participants must abstain from smoking 5 days prior to admission and throughout the confinement period, and test negative on Day -1 for urine cotinine test. Participants must also abstain from smoking 72 hours prior to each outpatient visit;
7. Participants must agree to abstain from alcohol intake from 48 hours prior to admission and during the confinement period;
8. Women of childbearing potential (WOCBP) must be non-pregnant and must use an acceptable, highly effective double contraception from Screening until study completion, including the follow up period.
9. Males must not donate sperm for at least 90 days after the last dose of study drug;
10. Participants must have the ability and willingness to attend the necessary visits to the CRU;
11. Participants must be willing and able to provide written informed consent after the nature of
the study has been explained and prior to the commencement of any study procedures.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Prior or ongoing medical conditions, medical history, physical findings, or laboratory abnormality that, in the Investigator’s (or delegate’s) opinion, may require treatment or render the participant unlikely to fully complete the study, or any condition that presents undue risk from the IP or procedures or interfere with study assessments;
2. Confirmed diagnosis of diabetes mellitus type 1, type 2, or of any other forms at any time, and/or occurrence of documented or suspected hypoglycaemic episodes within 12 months prior to Screening;
3. Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2;
4. History of acute or chronic pancreatitis;
5. Participants must be willing not to undertake any strenuous exercise, including but not limited to weightlifting (greater than 5 times per week) within 5 days prior to first study drug administration and for the duration of the study (including the follow-up period);
6. Participants must not start or having started participation in any medical (e.g., assisted by a clinical dietician or nutritionist) or non-medical (e.g., by a gym coach) diet and/or exercise programme within 3 months prior to Screening and for the duration of the study (including the follow-up period);
7. Use and/or planned use of any approved or unapproved weight-lowering medication(s) (including but not limited to orlistat, sibutramine, rimonabant, phentermine, or liraglutide) and/or medical device(s) within 3 months prior to Screening and for the duration of the study (including the follow-up period);
8. Previous history of any major gastrointestinal (including hepatobiliary and/or pancreatic) surgeries, including but not limited to sleeve, subtotal, or total gastrectomy, gastrojejunostomy, gastroduodenectomy, gastroduodenostomy, jejunectomy, ileectomy (proto)colectomy, hepatectomy, and pancreatectomy (except for appendectomy or cholecystectomy) and planned performance of one or more of the above mentioned for the duration of the study (including the follow-up period);
9. History of cerebral stroke (including but not limited to cerebral infarction/haemorrhage) within 12 months prior to Screening;
10. History of acute coronary syndrome (angina pectoris/myocardial infarction) and any other major cardiac conditions (including but not limited to myocarditis, cardiac insufficiency/failure, and any clinically significant arrythmia[s]) within 12 months prior to Screening;
11. Systolic blood pressure (BP) greater than 140 mmHg and/or less than 90 mmHg and/or diastolic BP greater than 90 mmHg and/or less than 40 mmHg and/or pulse rate greater 100 bpm and/or less than 40 bpm at Screening with one repeat allowed per by the Investigator or delegate at Screening and/or on Admission
12. Any clinically significant arrhythmia(s) at Screening ECG; specifically, the participant's
corrected QT interval (QTcF) (Fridericia's correction) is greater than 450 ms at Screening and on Day -1. An out-of-range or abnormal ECG may be repeated during Screening. On admission, three ECGs should be recorded consecutively, and the Investigator must evaluate the triplicate ECG. If the participant's QTcF is greater than 450 ms on at least two ECGs, the participant must be excluded;
13. Any medically uncontrolled respiratory disease(s) and/or condition(s), including but not limited to severe current asthma, chronic obstructive pulmonary disease, and obstructive sleep apnoea syndrome;
14. Fever (body temperature greater than 38°C) or symptomatic viral or bacterial infection within 2 weeks prior to Screening;
15. Clinically significant gastrointestinal disease(s), including but not limited to inflammatory bowel disease, irritable bowel syndrome, celiac disease, dyspepsia, apparent diabetic gastroparesis, and diabetic diarrhoea;
16. With alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or alkaline
phosphatase (ALP) greater than 1.5 × upper limit of normal (ULN) at Screening. Repeat testing at Screening is acceptable for out of range values following approval by the Investigator or delegate;
17. With a confirmed creatinine clearance (CLcr) using the Cockcroft-Gault equation below
90 mL/min. Repeat testing at Screening is acceptable for out of range values following approval by the Investigator or delegate;
18. History of clinically significant endocrine condition(s), including but not limited to hyper/hypothyroidism and/or hyper/hypoadrenalism;
19. History of primary or recurrent malignancy, except for non-melanoma skin cancer excised more than 2 years prior to Screening and/or cervical intraepithelial neoplasia having been successfully cured more than 5 years prior to Screening;
20. With clinically significant haematologic abnormalities, including but not limited to
haemoglobin above 180 g/L and/or below 110 g/L, white blood cell count (WBC) above
10.5×10^9/L and/or below 3.5×10^9/L, absolute neutrophil count above 7.0×10^9/L and/or below 2.0×10^9/L, and/or platelet count above 300×10^9/L and/or below 130×10^9/L. Repeat testing at Screening is acceptable for out of range values following approval by the Investigator or delegate;
21. With any other clinically significant laboratory abnormalities in clinical biochemistry,
coagulation function, and/or urinalysis. Repeat testing at Screening is acceptable for out of
range values following approval by the Investigator or delegate;
22. With positive test result(s) for hepatitis C virus (HCV) antibody, hepatitis B surface antigen
(HBsAg), or human immunodeficiency virus (HIV) antibody at Screening;
23. History of life-threatening infection (e.g. meningitis) and/or any major infections requiring
parental antimicrobials within 6 months prior to Screening;
24. Regular alcohol consumption (by self-declaration) defined as greater than 21 alcohol units per week (where 1 unit = 284-mL of beer, 25-mL of 40% spirit or a 125-mL glass of wine). Participant is unwilling to abstain from alcohol beginning 48 hours prior to admission to the CRU and during the confinement period;
25. With a history of substance abuse or dependency in the last 12 months, or a history of
recreational intravenous drug use over the last 5 years (by self-declaration);with a positive
toxicology screening panel (urine test including qualitative identification of barbiturates,
tetrahydrocannabinol [THC], amphetamines, methamphetamines, methylenedioxy-methamphetamine [MDMA], phencyclidine, benzodiazepines, opiates and cocaine), or alcohol breath test;
26. History of severe allergic or anaphylactic reactions;
27. Known or suspected intolerance or hypersensitivity to the IP, close related compounds, or any of the stated ingredients;
28. Blood donation or significant blood loss (greater than or equal to 400 mL) within 60 days prior to the first study drug administration;
29. Plasma donation within 7 days prior to the first study drug administration;
30. Being pregnant or lactating at Screening or planning to become pregnant (self or partner) at any time during the study and for at least 3 months after the last dose of study drug;
31. Use of any IP or investigational medical device within 30 days prior to Screening, or 5 half lives of the product (whichever is the longest) or participation in more than four investigational drug studies within 1 year prior to Screening;
32. Previous treatment with glucagon-like peptide 1 (GLP-1) agonists within the last 3 months;
33. Use of any prescription drug(s) and medical device(s) (other than hormonal contraception:
OCPs, long-acting implantable hormones, injectable hormones, a vaginal ring, or an IUD)
within 2 weeks prior to the first study drug dosing or use of any over the-counter (OTC)
medication, herbal remedies, supplements or vitamins within 1 week prior to the first study
drug dosing and during the course of the study without prior approval of the Investigator and
MM. Use of simple analgesic(s) (e.g., paracetamol, a nonsteroidal anti-inflammatory drug
[NSAID]) may be permitted at the discretion of the Investigator;
34. Present comedication with drugs known to interfere with glucose metabolism, such as systemic corticosteroids, non-selective beta-blockers, and monoamine oxidase inhibitors;
35. Presence of any underlying physical and/or psychological medical condition that, in the opinion of the Investigator, would make it unlikely that the subject will comply with the protocol or complete the study per protocol.

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
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
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
28/03/2020
Actual
Date of last participant enrolment
Anticipated
1/12/2020
Actual
Date of last data collection
Anticipated
31/12/2020
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,VIC
Recruitment hospital [1] 15714 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 29135 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 304805 0
Commercial sector/Industry
Name [1] 304805 0
Sciwind Biosciences APAC CO Pty. Ltd.
Country [1] 304805 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Sciwind Biosciences APAC CO Pty. Ltd.
Address
Sciwind Biosciences APAC CO Pty. Ltd.
58 Gipps Street
Collingwood, VIC 3066, Australia
Country
Australia
Secondary sponsor category [1] 305143 0
None
Name [1] 305143 0
NA
Address [1] 305143 0
NA
Country [1] 305143 0
Other collaborator category [1] 281150 0
Commercial sector/Industry
Name [1] 281150 0
Novotech (Australia) Pty Limited
Address [1] 281150 0
Level 3, 235 Pyrmont Street, Pyrmont NSW 2009
Country [1] 281150 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305220 0
The Alfred HREC
Ethics committee address [1] 305220 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 305220 0
Australia
Date submitted for ethics approval [1] 305220 0
31/01/2020
Approval date [1] 305220 0
11/02/2020
Ethics approval number [1] 305220 0

Summary
Brief summary
This is a first-in-human (FIH), single-centre, double blind, randomised, SAD study of XW003 conducted in healthy adult participants. The study is designed to evaluate the safety, tolerability, PK, and PD of XW003 in healthy participants. Oversight for the study will be provided by a Safety Review Committee (SRC) comprised of the Investigator, the Sponsor’s Medical Monitor (MM) and an independent MM.
XW003 is an acylated human GLP-1 analogue and is being development for obesity management. Native GLP-1 is a gut-derived incretin hormone that stimulates insulin secretion and suppresses glucagon secretion in a glucose dependent manner. It is also known to delay gastric emptying and reducing appetite and energy intake. These actions improve glucose homeostasis and thereby reduce hyperglycaemia, making GLP 1 an attractive substance in the management of obesity and associated morbidities. There is enough pre-clinical evidence that XW003 to justify the safety and therefore it is now being tested in humans.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 99658 0
Dr Benjamin Snyder
Address 99658 0
Centre for Clinical Studies (AMREP)
Level 5 Burnet Institute
89 Commercial Road, Melbourne
Victoria 3004, Australia
Country 99658 0
Australia
Phone 99658 0
+61 3 8593 9838
Fax 99658 0
+61 3 9 076 8911
Email 99658 0
[email protected]
Contact person for public queries
Name 99659 0
Benjamin Snyder
Address 99659 0
Centre for Clinical Studies (AMREP)
Level 5 Burnet Institute
89 Commercial Road, Melbourne
Victoria 3004, Australia
Country 99659 0
Australia
Phone 99659 0
+61 3 8593 9838
Fax 99659 0
+61 3 9 076 8911
Email 99659 0
[email protected]
Contact person for scientific queries
Name 99660 0
Benjamin Snyder
Address 99660 0
Centre for Clinical Studies (AMREP)
Level 5 Burnet Institute
89 Commercial Road, Melbourne
Victoria 3004, Australia
Country 99660 0
Australia
Phone 99660 0
+61 3 8593 9838
Fax 99660 0
+61 3 9 076 8911
Email 99660 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
No additional documents have been identified.