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Trial registered on ANZCTR


Registration number
ACTRN12622000392763
Ethics application status
Approved
Date submitted
24/02/2022
Date registered
7/03/2022
Date last updated
5/04/2023
Date data sharing statement initially provided
7/03/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1 Single and Multiple Ascending Dose Study to Assess the Safety and Pharmacokinetics of SZN-043, a Novel Bispecific Fusion Protein Targeting ASGR1 and ZNRF3/RNF43, in Healthy Volunteers and Subjects with Liver Cirrhosis
Scientific title
A Phase 1 Single and Multiple Ascending Dose Study to Assess the Safety and Pharmacokinetics of SZN-043, a Novel Bispecific Fusion Protein Targeting ASGR1 and ZNRF3/RNF43, in Healthy Volunteers and Subjects with Liver Cirrhosis
Secondary ID [1] 306483 0
CL-0043-1001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alcoholic Hepatitis 325342 0
Liver Cirrhosis 325343 0
Condition category
Condition code
Inflammatory and Immune System 322727 322727 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part 1: Single doses of SZN-043 will be administered via intravenous injection. Each dose level will be tested within one cohort. Each patient will only be assigned one dose level. Escalating dose cohorts will be explored as low as 1mg/kg up to 10mg/kg, increments varying by tolerability and PK data. Progression between cohorts will commence based upon recommendation of the SRC based on its review of safety data after all patients in the preceding cohort have been observed for at least 14 days after dose. All dosing is performed while patients are confined in the clinical trial unit for a period prior and after dosing.

Part 2: Multiple doses (6) of SZN-043 will be administered via intravenous injection. Dosing will occur on Days 0, 14, 17, 21, 24 and 28. Part 2 may commence upon recommendation of the SRC based on its review of all safety data after a higher dose cohort in Part 1 has completed dosing, and the last participant has been observed for 14 days. Each patient will only be assigned one dose level. Dose cohorts will increase through a dose not higher in exposure than doses considered safe to progress in Part 1. Progression between cohorts will commence based upon recommendation of the SRC based on its review of safety data after all patients in the preceding cohort have been observed for at least 14 days after their last dose. All dosing is performed while patients are confined in the clinical trial unit for a period prior and after dosing.
Intervention code [1] 322906 0
Treatment: Drugs
Comparator / control treatment
Placebo will be in the form of normal saline (0.9% solution for injection), administered in the same manner and with the same volume as the study drug for the given cohort.
Control group
Placebo

Outcomes
Primary outcome [1] 330530 0
Parts 1 and 2: Safety and tolerability of SZN-043 in HVs (Part 1) and patients with Cirrhosis (Part 2), based on the frequency and severity of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), electrocardiograms (ECGs), and treatment-emergent laboratory and physical examination findings. Adverse events may include reactions to study drug, injection or infusion site reactions, etc. Events will be assessed based on investigator observation and patient self report. AEs will be graded in accordance with CTCAE criteria.
Timepoint [1] 330530 0
Part 1: The safety observations of all types that are assessed by the investigator or reported by the site will be assessed at least every other week, with TEAEs and TESAEs assessed at every contact with the subject until 4 weeks post dose.
Part 2: The safety observations of all types that are assessed by the investigator or reported by the site will be assessed at least every other week, with TEAEs and TESAEs assessed at every contact with the subject until 4 weeks post last dose.
Primary outcome [2] 330531 0
Parts 1 and 2: The maximum tolerated dose (MTD) of SZN-43 in HV
Timepoint [2] 330531 0
Part 1 and 2: The maximum tolerated dose (MTD) of SZN-043 will be defined as the dose below which 2 or greater subjects experience a treatment-related TEAE (NCI CTCAE equals grade 3 or higher) occurring within 14 days of administration of SZN 043, except for isolated alkaline phosphatase (ALP) elevations.
Secondary outcome [1] 406532 0
Pharmacokinetic parameters (measured from blood serum) in HVs following a single IV dose (Part 1) and in participants with liver cirrhosis following single dose of SZN-043, as data allow. PK Parameters assessed will include but are not limited to Cmax, Clast, Tmax, AUC0-last, AUC0-inf, CL, CLss, t1/2,, etc. as available data allow.
Timepoint [1] 406532 0
Part 1 (IV): PK will be measured on Day 0 (day of dosing) once pre-dose, and post-dose (end of administration): 5 min (± 5 minutes), 30 mins (±5 minutes), 2 hours (±5 minutes), 4 hours (± 10 minutes), 8 hours (± 10 minutes), 12 hours (± 10 minutes), and then on Days 1, 2, 3, 5, 7, 14, 21, and 28.

Part 2: PK will be measured on Day 0 (day of dosing), once pre-dose and post-dose (end of administration): 5 min (± 5 minutes), 30 mins (±5 minutes), 2 hours (±5 minutes), 4 hours (±10 minutes), 8 hours (± 10 minutes), 12 hours (± 10 minutes), then on Days 1, 2, 3, 5, 7, 14, 21, 28, 29, 31, 33, 35, and 56.
Secondary outcome [2] 406534 0
Prevalence of Anti-Drug Antibodies (measured in blood serum) for SZN-043 in HVs (Part 1) and subjects with liver cirrhosis (Part 2) at baseline and incidence of ADA during the study.
Timepoint [2] 406534 0
Part 1 (IV and SC): ADA will be measured on Day 0 (day of dosing) once predose, and at Day 14 and 28.
Part 2: ADA will be measured on Day 0 (day of dosing) once pre-dose, and at Day 14, 28, 35 and 56.

Eligibility
Key inclusion criteria
Part 1:
1. Healthy male or female volunteers.

Part 2:
1. Males or female with documented history of liver cirrhosis and a Child-Pugh score between 5 and 7, inclusive, at screening.
2. A fibroscan of equal to or greater than 6kPa.
3. MELD Score of equal to or less than 12 at Screening based on local lab results.
Minimum age
18 Years
Maximum age
50 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Part 1 (Healthy Volunteers)
1. Pregnant or lactating at Screening or planning to become pregnant (self or partner) at any time during the study.
2. Previous receipt of antibody or biologic therapy whether licensed or investigational (immunoglobulin products, monoclonal antibodies or antibody fragments) within the past 6 months.
3. History of hyperthyroidism, Paget’s disease, osteomalacia, or fracture within 4 weeks of Screening.
4. A QT duration corrected for heart rate by Fridericia's formula (QTcF) >450 msec for males and >470 msec for females based on either single or averaged QTcF values of triplicate ECGs prior to study drug administration.
5. Regular excessive alcohol consumption within 6 months of the study defined as an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 grams (g) of alcohol: a half-pint ~240 mL of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
6. A history of malignant neoplasm, except for adequately treated non-metastatic basal or squamous cell cancers of the skin (>1 year ago) or carcinoma in situ of the uterine cervix (>3 years ago) that has been fully treated and shows no evidence of recurrence. Subjects under evaluation for possible malignancy are not eligible.

Part 2: Subjects with Liver Cirrhosis
1. Cirrhosis from biliary aetiology.
2. Pregnant or lactating at Screening or planning to become pregnant (self or partner) at any time during the study.
3. Previous receipt of antibody or biologic therapy whether licensed or investigational (immunoglobulin products, monoclonal antibodies or antibody fragments) within the past 6 months.
4. History of hyperthyroidism, Paget’s disease, osteomalacia, or fracture within 4 weeks of Screening.
5. Use of controlled substances (including inhaled or injected drugs), or non-prescribed use of prescription drugs within previous 12 months.
6. History of alcohol consumption within 3 months prior to Screening for subjects with cirrhosis due to alcoholic liver disease.
7 A history of malignant neoplasm, except for adequately treated non-metastatic basal or squamous cell cancers of the skin (>1 year ago) or carcinoma in situ of the uterine cervix (> 3 years ago) that has been fully treated and shows no evidence of recurrence.
8. Hepatic mass(es) evident on liver imaging (ultrasound) at Screening.
9. Previous liver transplantation.
10. Active or recent (within 14 days of Screening) gastrointestinal bleeding.
11. Subjects with portal vein thrombosis.
12. Subjects with a portosystemic shunt or scheduled for transjugular intrahepatic portosystemic shunt (TIPS) placement during the study period.
13. Requirement for renal replacement therapy.
14. Current use of anticoagulants that affect prothrombin time or international normalised ratio.
15. Extensive resection of large segments of small intestine (short gut) or severe gastroparesis.

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)
A randomisation and trial supply management module in the EDC will manage the randomisation of eligible study subjects. Treatment assignment will not be known to the investigators or patients.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation.
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
Other
Other design features
Participants are assigned to one cohort, defined by dose and administration type. Dose cohorts are completely enrolled prior to the next cohort. Dose cohorts from Part 1 through Part 2 are enrolled sequentially such that the next higher dose is enrolled only once enrollment and observation has completed in the previous cohort.
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
The sample size for this study is based on dose escalation rules and not based on any statistical criteria.

Statistical analyses will be descriptive in nature. Summaries will be provided for subject disposition, demographics, baseline characteristics, safety, PK, PD, and ADA parameters and presented by cohort and treatment group.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
6/06/2022
Actual
6/06/2022
Date of last participant enrolment
Anticipated
9/09/2023
Actual
Date of last data collection
Anticipated
9/11/2023
Actual
Sample size
Target
40
Accrual to date
16
Final
Recruitment outside Australia
Country [1] 24602 0
New Zealand
State/province [1] 24602 0
Auckland

Funding & Sponsors
Funding source category [1] 310830 0
Commercial sector/Industry
Name [1] 310830 0
Surrozen Operating, Inc.
Country [1] 310830 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Surrozen Operating, Inc.
Address
171 Oyster Point Boulevard, Suite 400
South San Francisco, CA 94080
United States
Country
United States of America
Secondary sponsor category [1] 312079 0
Commercial sector/Industry
Name [1] 312079 0
Novotech (Australia) Pty Limited
Address [1] 312079 0
Level 3, 235 Pyrmont Street
Pyrmont NSW 2009
Australia
Country [1] 312079 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310394 0
Northern A Health and Disability Ethics Committee
Ethics committee address [1] 310394 0
Ethics committee country [1] 310394 0
New Zealand
Date submitted for ethics approval [1] 310394 0
03/03/2022
Approval date [1] 310394 0
20/04/2022
Ethics approval number [1] 310394 0
2022 FULL 12266

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

Contacts
Principal investigator
Name 117506 0
Prof Edward Gane
Address 117506 0
New Zealand Clinical Research
3 Ferncroft Street,
Grafton 1010
Auckland
Country 117506 0
New Zealand
Phone 117506 0
+64 09 529 4001
Fax 117506 0
+64 09 307 8936
Email 117506 0
[email protected]
Contact person for public queries
Name 117507 0
Edward Gane
Address 117507 0
New Zealand Clinical Research
3 Ferncroft Street,
Grafton 1010
Auckland
Country 117507 0
New Zealand
Phone 117507 0
+64 09 529 4001
Fax 117507 0
+64 09 307 8936
Email 117507 0
[email protected]
Contact person for scientific queries
Name 117508 0
Edward Gane
Address 117508 0
New Zealand Clinical Research
3 Ferncroft Street,
Grafton 1010
Auckland
Country 117508 0
New Zealand
Phone 117508 0
+64 09 529 4001
Fax 117508 0
+64 09 307 8936
Email 117508 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
Privacy and intellectual property considerations


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.