Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000194561p
Ethics application status
Submitted, not yet approved
Date submitted
31/01/2024
Date registered
28/02/2024
Date last updated
28/02/2024
Date data sharing statement initially provided
28/02/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A Multiple Dose Study in Participants with Severe Alcohol-Associated Hepatitis to Assess the Safety and the Way the Body Absorbs, Distributes, and Eliminates the drug SZN-043.
Scientific title
A Phase 1b Multiple Ascending Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of SZN-043 in Participants with Severe Alcohol-Associated Hepatitis
Secondary ID [1] 311416 0
CL-0043-1002
Universal Trial Number (UTN)
U1111-1303-3987
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Severe Alcohol-Associated Hepatitis 332697 0
Condition category
Condition code
Oral and Gastrointestinal 329407 329407 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
SZN-043 is a is an antibody fusion protein that is an RSPO mimetic specifically targeted to hepatocytes through ASGR1 binding. SZN-043 will be administered via intravenous injection. Doses of 0.5mg/kg, 1.0mg/kg, and 1.5mg/kg are planned to be tested in 3 separate cohorts, twice within one week (Day 0, Day 4). The product is administered and observed by qualified staff in an in an inpatient setting. Optional cohorts are possible to test other doses and frequencies to be determined by review of available data. The frequency may increase to as much as 3x (Day 0, 4, and 7) or decrease. The determination of the frequency and of the exact dose will be made based on emerging safety data, PK data, and/or other indicators with respect to patient outcomes from the preceding cohorts. The maximum exposure will not exceed a dose equivalant of 3,0mg/kg.
Intervention code [1] 327855 0
Treatment: Drugs
Comparator / control treatment
No control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 337225 0
To evaluate the safety of MAD of SZN-043 in participants with severe alcohol-associated hepatitis.
Timepoint [1] 337225 0
Laboratory assessments are conducted from baseline and thereafter daily through Day 9, D11, D14, D18. D21, D28, d60, and D90.
Physical Examinations are conducted at baseline and at end of study.
Vital signs are monitored on days of dosing, as required on lab visit days, but at least at Day 7, Day 28, Day 60 and Day 90.
ECGs are conducted on days of dosing, and at end of study.
All adverse events, reported by participants and/or observed by clinical staff will reported through end of study participation.
Primary outcome [2] 337402 0
To evaluate the Tolerability of MAD of SZN-043 in participants with severe alcohol-associated hepatitis
Timepoint [2] 337402 0
Continual assessment from the start of dose through 4 hours post dose.
Secondary outcome [1] 431120 0
To assess the change from baseline in alcohol-associated hepatitis disease progression within and across cohorts as measured by Model for End-Stage Liver Disease (MELD).
Timepoint [1] 431120 0
Percent and absolute change in MELD score from baseline toDays 4, 7, 28, 60, and 90.
Secondary outcome [2] 431121 0
To assess the change from baseline in functional measures of liver function within and across cohorts as measured by ALT.
Timepoint [2] 431121 0
Laboratory assessments are conducted from baseline and thereafter daily through Day 9, D11, D14, D18. D21, D28, d60, and D90.
Secondary outcome [3] 431122 0
To characterize the PK of SZN-043
Timepoint [3] 431122 0
Measured from Day 0 (prior to dose) through Day 35, at least daily on Days 0 through Day 9, 11, 14, 21, 28, and end of study. Day 35 may be added if a dose on Day 7 is added based on the cohort design.
Secondary outcome [4] 431123 0
To evaluate immunogenicity (measured as ADA) to SZN-043
Timepoint [4] 431123 0
Measured once Pre-Dose, and again on Day 14, 28, 60 and 90.
Secondary outcome [5] 431723 0
To assess the change from baseline in functional measures of liver function
within and across cohorts as measured by AST.
Timepoint [5] 431723 0
Laboratory assessments are conducted from baseline and thereafter daily through Day 9, D11, D14, D18. D21, D28, d60, and D90.
Secondary outcome [6] 431726 0
To assess the change from baseline in functional measures of liver function within and across cohorts as measured by international normalised ratio (INR)
Timepoint [6] 431726 0
Laboratory assessments are conducted from baseline and thereafter daily through Day 9, D11, D14, D18. D21, D28, d60, and D90.
Secondary outcome [7] 431727 0
To assess the change from baseline in functional measures of liver function within and across cohorts as measured by albumin.
Timepoint [7] 431727 0
Laboratory assessments are conducted from baseline and thereafter daily through Day 9, D11, D14, D18. D21, D28, d60, and D90.
Secondary outcome [8] 431728 0
To assess the change from baseline in alcohol-associated hepatitis disease progression within and across cohorts as measured by Lille Model for alcohol-associated hepatitis (Lille) score
Timepoint [8] 431728 0
Calculate Lille Model Score on Days 0, 4, and 7 to determine percent and absolute change from baseline to Days, 4 and 7 respectively, and percent of participants with Lille Model Score <0.45 at Days 4 and 7.
Secondary outcome [9] 431732 0
To assess the change from baseline in alcohol-associated hepatitis disease progression within and across cohorts as measured by mortality.
Timepoint [9] 431732 0
Calculate percent of participants alive at Days 28, 60, and 90

Eligibility
Key inclusion criteria
1. Male or female (sex assigned at birth), 18 years of age or older AND considered to be an adult in accordance with local law.
2. BMI between 18.0 and 36.0 kg/m2, inclusive, at Screening.
3. A clinical diagnosis of AH that is anticipated to require inpatient care for a period to encompass at a minimum the first dose of study drug based on typical serum chemistry (as determined by local laboratory) meeting all of the following parameters:
a. Onset of jaundice within prior 8 weeks;
b. History of heavy alcohol abuse: >40 (female) or 60 (male) g alcohol/day for greater than or equal to 6 months;
c. Consumed alcohol within 8 weeks before study entry;
d. AST >50, AST/ALT >1.5, and both values are: <400 IU/L, and
e. Serum total bilirubin >3.0 mg/dL.
4. MELD score of 21 to 30, inclusive.
5. Willing to use acceptable methods of contraception or not physically able to conceive or impregnate others.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Previous receipt of antibody or biologic therapy within the past 6 months
2. Treatment with any experimental drug within 30 days, or within 5 half-lives (whichever is longer), before Day 0 visit (Baseline).
3. Other causes of liver disease
4. Recent start of liver toxic medications
5. Have a portosystemic shunt or scheduled for transjugular intrahepatic portosystemic shunt placement or highly likely to receive a liver transplant during the study.
6. Dependent upon inotropic support (including selepressin or terlipressin) or ventilatory or vasopressor support.
7. Organ failure (as defined by hepatic encephalopathy >stage 3) or requires renal replacement therapy or creatinine >2.5 mg/dL (or 221 mmol/L).
8. Uncontrolled hyperthyroidism, history of Paget's disease, osteomalacia, or fracture within 4 weeks of Screening.
9. Uncontrolled bacterial infections, as determined by the investigator's judgment after a minimum of 2 days of antibiotic therapy.
10. History of a previous severe allergic reaction with generalised urticaria, angioedema, or anaphylaxis.
11. 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 before study drug administration.
12. A history of malignant neoplasm, evidence of recurrence of certain skin cancers, or under investigation for a malignancy.
13. Gastrointestinal (GI) bleeding within 2 days of Screening requiring transfusion of more than 3 units of blood.
14. Grade 3 or higher encephalopathy by West Haven Criteria.
15. Acute kidney injury defined as an increase in serum creatinine (sCr) greater than or equal to 0.3 mg/dL within 48 h or increase in sCr greater than or equal to 50% from baseline known or presumed
16. Presence of portal vein thrombosis.
17. Presence of acute pancreatitis.
18. Cerebral hemorrhage, extensive retinal hemorrhage, acute myocardial infarction (within
the last 6 weeks) or severe cardiac arrhythmias (not including atrial fibrillation).
19. Evidence of GI bleeding or renal failure after 7 days of treatment within 8 weeks of screening.
20. Liver imaging at screening showing any lesions (except benign lesions, i.e., hemangiomas).
21. Known infection with HIV or HIV Ab positive at screening .
22. Organ transplantation (such as liver, kidney, lung, heart, bone marrow, or stem cell etc.), other than cornea transplant.
23. Positive urine screen for amphetamines, cocaine, or non-prescribed opiates.
24. Pregnant or lactating at Screening or planning to become pregnant (self or partner) at any time during the study.
25. Planning to donate sperm (male) or ovum (female) within 90 days after the last dose of study drug.
26. Current use of anticoagulants that affect prothrombin time or international normalised ratio (INR).
27. Eligibility: All participants where HepQuant SHUNT test kit use is specified:
a. Extensive resection of large segments of small intestine (short gut) or severe
gastroparesis; On either a non-selective beta blocker or an angiotensin-converting
enzyme inhibitor or angiotensin II receptor blockers who are unwilling or unable
to delay taking their normal dose the morning of the HepQuant SHUNT test;
b. Allergy to any ingredient in the formulations or components in the HepQuant Lab
Developed kit.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised 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
Open (masking not used)
Who is / are masked / blinded?



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

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
30/03/2024
Actual
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
31/03/2025
Actual
Sample size
Target
18
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD
Recruitment outside Australia
Country [1] 26113 0
New Zealand
State/province [1] 26113 0
Country [2] 26114 0
Canada
State/province [2] 26114 0
Country [3] 26115 0
Korea, Republic Of
State/province [3] 26115 0
Country [4] 26116 0
United Kingdom
State/province [4] 26116 0

Funding & Sponsors
Funding source category [1] 315676 0
Commercial sector/Industry
Name [1] 315676 0
Surrozen Operating, Inc.
Country [1] 315676 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Surrozen Operating, Inc.
Address
Country
United States of America
Secondary sponsor category [1] 317780 0
Commercial sector/Industry
Name [1] 317780 0
Novotech (Australia) Pty Limited
Address [1] 317780 0
Country [1] 317780 0
Australia
Secondary sponsor category [2] 317783 0
Commercial sector/Industry
Name [2] 317783 0
Novotech (New Zealand) Limited
Address [2] 317783 0
Country [2] 317783 0
New Zealand
Secondary sponsor category [3] 317784 0
Commercial sector/Industry
Name [3] 317784 0
Novotech Asia Korea Co., Limited
Address [3] 317784 0
Country [3] 317784 0
Korea, Republic Of

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 314555 0
Northern B Health and Disability Ethics Committee 
Ethics committee address [1] 314555 0
https://ethics.health.govt.nz/about/northern-b-health-and-disability-ethics-committee/
Ethics committee country [1] 314555 0
New Zealand
Date submitted for ethics approval [1] 314555 0
19/01/2024
Approval date [1] 314555 0
Ethics approval number [1] 314555 0
Ethics committee name [2] 314556 0
Metro North Health Human Research Ethics Committee A
Ethics committee address [2] 314556 0
https://metronorth.health.qld.gov.au/research/ethics-and-governance/human-research-ethics-committee
Ethics committee country [2] 314556 0
Australia
Date submitted for ethics approval [2] 314556 0
30/01/2024
Approval date [2] 314556 0
Ethics approval number [2] 314556 0

Summary
Brief summary
Severe alcohol-associated hepatitis (SAH) is a huge unmet medical need, associated with high mortality. Corticosteroids have not been associated with improved long-term survival benefit and there has been no improvement in survival in SAH with medical management during the last 60 years. SAH is associated with impaired growth of new cells in your liver (known as hepatocyte proliferation). Elevated Wnt signaling and increased hepatocyte proliferation have been linked to greater survival, suggesting that therapies that can enhance hepatocyte proliferation can benefit patients. R-spondins (RSPOs) are known enhancers of Wnt signaling. SZN-043 is a bispecific fusion protein and hepatocyte-specific RSPO mimetic shown to bring on hepatocyte-targeted Wnt signaling and hepatocyte proliferation in research studies performed in laboratories. SZN-043 was evaluated for safety and how the drug behaves in the human body in a single center, first-in-human study in healthy volunteers and patients with mild cirrhosis of the liver. This second study will evaluate the same things in patients who have severe AH.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 131998 0
Prof Juan Pablo Arab
Address 131998 0
Division of Gastroenterology and Hepatology, Multiorgan Transplant Program, 339 Windermere Road, Room A10-224, Western University & London Health Sciences Centre, London, Ontario N6A 5A5
Country 131998 0
Canada
Phone 131998 0
+15196633946
Fax 131998 0
Email 131998 0
JP.Arab@lhsc.on.ca
Contact person for public queries
Name 131999 0
Joshua Koons
Address 131999 0
Surrozen Operating, Inc., 171 Oyster Point Blvd, Ste 400, South San Francisco, CA 94708
Country 131999 0
United States of America
Phone 131999 0
+16504207056
Fax 131999 0
Email 131999 0
Joshua@surrozen.com
Contact person for scientific queries
Name 132000 0
Craig Parker
Address 132000 0
Surrozen Operating, Inc., 171 Oyster Point Blvd, Ste 400, South San Francisco, CA 94708
Country 132000 0
United States of America
Phone 132000 0
+16504437353
Fax 132000 0
Email 132000 0
Craig@surrozen.com

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.