Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000295943
Ethics application status
Approved
Date submitted
31/07/2019
Date registered
4/03/2020
Date last updated
3/04/2023
Date data sharing statement initially provided
4/03/2020
Date results information initially provided
3/04/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A Multiple Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AB-729 Administered by Subcutaneous Injection to Subjects with Chronic Hepatitis B Infection
Scientific title
Part 3 of a three part study-- A Multiple Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AB-729 Administered by Subcutaneous Injection to Subjects with Chronic Hepatitis B Infection
Secondary ID [1] 298573 0
AB-729-001
Universal Trial Number (UTN)
U1111-1227-7086
Trial acronym
Linked study record
ACTRN12619000954123 and ACTRN12619001197123
It is the third part of the study, as in this study there are 3 parts.

Health condition
Health condition(s) or problem(s) studied:
Chronic Hepatitis B Infection (CHB) 313412 0
Condition category
Condition code
Infection 311847 311847 0 0
Other infectious diseases
Oral and Gastrointestinal 311848 311848 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
The study will be conducted in 3 parts. Part 3 will be an open-label, Multiple Dose (MD) design and will be conducted in approximately 35 non-cirrhotic CHB infected subjects in up to 5 cohorts (E, F, I, J and G). Part 3 will range from approximately 35 to 102 weeks including Screening and optional treatment extension. Part 3 will commence after the study Safety Review Committee reviews all accumulated non-clinical and study safety and tolerability data up to and including at least 2 single dose cohorts of Part 2 and agrees to proceed. The doses in Cohorts E, F, I, J and G will not exceed those demonstrated to be safe in healthy subject Part 1. Each participant will receive multiple doses of AB-729 (a total of up to 6 doses); frequency of subcutaneous injection will be guided by single dose safety and viral pharmacodynamics in Part 2 but will not be more frequent than monthly.
All doses of AB-729 will be administered at the study site by study staff members.
Intervention code [1] 314833 0
Treatment: Drugs
Comparator / control treatment
None
Control group
Uncontrolled

Outcomes
Primary outcome [1] 320518 0
To evaluate the safety and tolerability of AB-729 following administration by SC injection of multiple doses (up to 6 months) to subjects with CHB infection as assessed by the frequency and severity of treatment emergent adverse events (TEAEs), discontinuations due to adverse events (AEs), and laboratory abnormalities.
Examples of known/possible adverse reactions/events:
This is a first in human study, so limited safety information about AB-729 is available. Possible adverse events based on similar compounds may include liver transaminase elevations, headache, or mild redness at the injection site. This will be assessed by clinical site staff during clinic visits and by participant diaries.
Timepoint [1] 320518 0
Part 3: Monitored during screening, Day 1, Day 3, Day 8, Weeks 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and possibly 24, 28, 32, 36, 40, 44 and 48 (if participating in the optional treatment extension), at Follow-up Weeks 2, 4, 6,8, 10, 12, and possibly 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, and 48 weeks after Last Dose.
Secondary outcome [1] 371902 0
To evaluate changes in concentration of HBsAg in subjects with CHB infection after multiple doses of AB-729 assessed by change from baseline in HBsAg.
Outcome Assessment: Serum assay tests will be used.
Timepoint [1] 371902 0
HBsAg will be performed throughout study at Screening and on Day 1, Day 3, and Day 8 and at Weeks 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and possibly 24, 28, 32, 36, 40, 44 and 48 (if participating in the optional treatment extension), at Follow-up Weeks 2, 4, 6, 8, 10, 12, and possibly 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, and 48 weeks after Last Dose
Secondary outcome [2] 371904 0
To characterize the multiple dose PK of AB-729 in subjects with CHB, e.g., maximum concentration [Cmax]), time to Cmax (Tmax), area under the concentration-time curve from time of dosing to the last measurable concentration [AUC(0-t)] and AUC(0-infinity)). Ctrough will also be evaluated at multiple timepoints
Timepoint [2] 371904 0
Plasma PK samples will be collected in the following timepoints: Predose (within 60 minutes prior to dosing), 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours and 6 hours after the first and last dose of AB-729, Day 3, Day 8, Weeks 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, and 20 and possibly 24, 28, 32, 36, 40, 44 and 48 (if participating in the optional treatment extension), Follow-up Visit Weeks 2, 4, 8, and 12.
Secondary outcome [3] 371905 0
To evaluate changes in concentration of HBV-RNA in subjects with CHB infection after multiple doses of AB-729 assessed by change from baseline.
Outcome assessment: Serum assay tests will be used.
Timepoint [3] 371905 0
Quantitative HBV-RNA test will be performed on Day 1, Day 3, Day 8, Weeks 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20 and possibly 24, 28, 32, 36, 40, 44 and 48 (if participating in the optional treatment extension), at Follow-up Weeks 2, 4, 6,8, 10, 12, and possibly 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, and 48 weeks after Last Dose
Secondary outcome [4] 371906 0
To evaluate changes in concentration of hepatitis B virus surface antibody in subjects with CHB infection after multiple doses of AB-729 assessed by change from baseline.
Outcome assessment: Serum assay tests will be used.
Timepoint [4] 371906 0
Quantitative HBsAb test will be performed on Day 1, Weeks 2, 3, 4, 6, 8, 10, 12, 14, 16, 18 20, and possibly 24, 28, 32, 36, 40, 44 and 48 (if participating in the optional treatment extension), at Follow-up Weeks 2, 4, 6, 8, 10, 12, and possibly 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, and 48 weeks after Last Dose.
Secondary outcome [5] 371907 0
To evaluate changes in concentration of Hepatitis B virus e antigen in subjects with CHB infection after multiple doses of AB-729 assessed by change from baseline.
Outcome assessment: Serum assay tests will be used.
Timepoint [5] 371907 0
Quantitative HBeAg test will be performed on Day 1, Day 3, Day 8, Weeks 2, 3, 4, 6, 8, 10, 12, 14, 16, 18 20, and possibly 24, 28, 32, 36, 40, 44 and 48 (if participating in the optional treatment extension), at Follow-up Weeks 2, 4, 6, 8, 10, 12, and possibly 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, and 48 weeks after Last Dose.
Secondary outcome [6] 371908 0
To evaluate changes in concentration of Hepatitis B virus e antibody in subjects with CHB infection after multiple doses of AB-729 assessed by change from baseline.
Outcome assessment: Serum assay tests will be used.
Timepoint [6] 371908 0
HBeAb test will be performed on Day 1,Weeks 2, 3, 4, 6, 8, 10, 12, 14, 16, 18 ,20, and possibly 24, 28, 32, 36, 40, 44 and 48 (if participating in the optional treatment extension), at Follow-up Weeks 2, 4, 6, 8, 10, 12, and possibly 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, and 48 weeks after Last Dose.
Secondary outcome [7] 371909 0
To evaluate changes in concentration of hepatitis B virus core-related antigen in subjects with CHB infection after multiple doses of AB-729 assessed by change from baseline.
Outcome assessment: Serum assay tests will be used.
Timepoint [7] 371909 0
Quantitative HBcrAg test will be performed on Day 1, Day 3, Day 8, Weeks 2, 3, 4, 6, 8, 10, 12, 14, 16, 18,20, and possibly 24, 28, 32, 36, 40, 44 and 48 (if participating in the optional treatment extension), at Follow-up Weeks 2, 4, 6, 8, 10, 12, and possibly 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, and 48 weeks after Last Dose.
Secondary outcome [8] 371910 0
Proportion of subjects with a change in HBsAg from baseline meeting response criteria (greater than or equal to 0.5, 1, 2, or 3 log10 reduction; less than or equal to lower limit of quantitation [LLOQ]).
Outcome assessment: Serum assay tests will be used.
Timepoint [8] 371910 0
Quantitative HBsAg test will be performed at Screening, Day 1, Day 3, Day 8,Weeks 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and possibly 24, 28, 32, 36, 40, 44 and 48 (if participating in the optional treatment extension), at Follow-up Weeks 2, 4, 6, 8, 10, 12, and possibly 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, and 48 weeks after Last Dose.
Secondary outcome [9] 371911 0
Proportion of subjects with a change in HBV-DNA from baseline meeting response criteria (greater than or equal to 0.5, 1, 2, or 3 log10 reduction; less than or equal to LLOQ.
Outcome assessment: Serum assay tests will be used.
Timepoint [9] 371911 0
Quantitative HBV-DNA test will be performed during Screening, on Day 1, Day 3, Day 8,Weeks 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and possibly 24, 28, 32, 36, 40, 44 and 48 (if participating in the optional treatment extension), at Follow-up Weeks 2, 4, 6, 8, 10, 12, and possibly 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, and 48 weeks after Last Dose.
Secondary outcome [10] 373165 0
To evaluate changes in concentration of HBV-DNA in subjects with CHB infection after multiple doses of AB-729 assessed by change from baseline in HBV-DNA.
Timepoint [10] 373165 0
Serum assay tests will be used. Quantitative HBV-DNA test will be performed during Screening, on Day 1, Day 3, Day 8, Weeks 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and possibly 24, 28, 32, 36, 40, 44 and 48 (if participating in the optional treatment extension), at Follow-up Weeks 2, 4, 6, 8, 10, 12, and possibly 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, and 48 weeks after Last Dose.

Eligibility
Key inclusion criteria
Inclusion Criteria for Study Part 3:
- Male subjects must agree to use contraception as detailed in the protocol.
- Female subjects must not be pregnant and must agree to use contraception as detailed in the protocol.
- BMI greater than or equal to 18 kg/m2 and lesser than or equal to 38 kg/m2.
- Documented chronic HBV infection as defined in the protocol
- HBV-DNA at screening: For HBV-DNA+ subjects (Cohorts G) only: HBV-DNA greater than or equal to 1,000 IU/mL at Screening. For HBV-DNA- subjects (Cohorts E, F, I and J) only: HBV-DNA must be lower than the limit of quantitation at Screening.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria for Study Part 3
Known co-infection with any of the following:
a. HIV,
b. acute hepatitis A virus (HAV),
c. HCV,
d. hepatitis D virus (HDV), OR
e. hepatitis E virus (HEV) infection.
Any known preexisting medical or psychiatric condition that could interfere with the subject’s ability to
provide informed consent or participate in study conduct, or that may confound study findings including,
but not limited to:
a. History of any clinically significant medical condition associated with chronic liver disease (e.g.,
hemochromatosis, autoimmune hepatitis, Wilson’s disease, a-1-antitrypsin deficiency, alcoholic liver
disease, non-alcoholic steatohepatitis, or toxin exposures) that may affect the ability to respond to HBV
therapy.
b. Immunologically mediated disease or significant immunosuppresion
d. Current or history of any clinically significant cardiac abnormalities/dysfunction or uncontrolled
hypertension.
e. Evidence of decompensated liver disease or findings suggestive of HCC at any time.
Evidence of active or suspected malignancy, or a history of malignancy
Findings/Diagnostic Assessments at Screening, confirmed by repeat testing:
- ALT or AST greater than 2 × upper limit of normal (ULN).
- Total bilirubin greater than 1.5 × ULN.
- Alpha fetoprotein (AFP) greater than 100 ng/mL.

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
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
20/04/2020
Actual
30/04/2020
Date of last participant enrolment
Anticipated
30/06/2021
Actual
26/06/2021
Date of last data collection
Anticipated
6/05/2025
Actual
Sample size
Target
96
Accrual to date
Final
43
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 14074 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [2] 14075 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [3] 14172 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment postcode(s) [1] 26865 0
2050 - Camperdown
Recruitment postcode(s) [2] 27148 0
3065 - Fitzroy
Recruitment postcode(s) [3] 26864 0
3168 - Clayton
Recruitment outside Australia
Country [1] 21639 0
Moldova, Republic Of
State/province [1] 21639 0
Country [2] 21641 0
Hong Kong
State/province [2] 21641 0
Country [3] 21642 0
Thailand
State/province [3] 21642 0
Country [4] 22383 0
New Zealand
State/province [4] 22383 0
Country [5] 22395 0
Korea, Republic Of
State/province [5] 22395 0

Funding & Sponsors
Funding source category [1] 303111 0
Commercial sector/Industry
Name [1] 303111 0
Arbutus Biopharma Corporation
Country [1] 303111 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Arbutus Biopharma Corporation
Address
701 Veterans Circle
Warminster, PA 18974 USA
Country
United States of America
Secondary sponsor category [1] 303105 0
None
Name [1] 303105 0
Address [1] 303105 0
Country [1] 303105 0
Other collaborator category [1] 280825 0
Commercial sector/Industry
Name [1] 280825 0
Novotech (Australia) Pty Limited
Address [1] 280825 0
Level 3, 235 Pyrmont Street, Pyrmont NSW 2009
Country [1] 280825 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303697 0
St Vincent's Hospital Melbourne Human Research Ethics Committee
Ethics committee address [1] 303697 0
PO Box 2900, 41 Victoria Parade, Fitzroy VIC 3065
Ethics committee country [1] 303697 0
Australia
Date submitted for ethics approval [1] 303697 0
02/04/2019
Approval date [1] 303697 0
30/05/2019
Ethics approval number [1] 303697 0
HREC 060/19
Ethics committee name [2] 305468 0
Northern B Health and Disability Ethics Committee
Ethics committee address [2] 305468 0
Ministry of Health, Level 3,Rangitoto Room, Unisys Building, 650 Great South Road, Penrose, Auckland
Ethics committee country [2] 305468 0
New Zealand
Date submitted for ethics approval [2] 305468 0
15/04/2020
Approval date [2] 305468 0
06/05/2019
Ethics approval number [2] 305468 0
19/NTB/45

Summary
Brief summary
The study drug AB-729 is being developed as a potential new treatment for Chronic Hepatitis B (CHB). The main goal of the study is to determine whether AB-729 is safe and well tolerated when given at different doses. We will also measure the levels of the drug in the blood at different times.
The study will be conducted in 3 parts.

Study Part 1 (Healthy Subjects SAD) : Part 1 will enroll 24 healthy subjects using a SAD design consisting of 4 sequential dose groups

Study Part 2 (Subjects with CHB Infection SAD): Once the safety and tolerability data from the first 2 doses of the SAD assessment in healthy subjects have been completed and it is considered safe to proceed by the SRC, Part 2 will commence in subjects with CHB infection.

Study Part 3 (Subjects with CHB Infection MD): Part 3 will be an open-label, Non-Randomized, MD design and will be conducted in 35 subjects with CHB infection.
Discontinuation of all HBV treatment is optional. If subjects stop all therapy, they will enter a more intensive follow-up period for 12 months and then have quarterly visits for up to 2 additional years for a total of up to 3 years of follow-up post-NA discontinuation
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 94422 0
Prof Edward Gane
Address 94422 0
Auckland Clinical Studies Ltd and Auckland City Hospital, PO Box 8963, Symonds St, Auckland, 1150
Country 94422 0
New Zealand
Phone 94422 0
+64 21548371
Fax 94422 0
Email 94422 0
EdGane@adhb.govt.nz
Contact person for public queries
Name 94423 0
Mr Michael Child
Address 94423 0
Arbutus Biopharma Corporation,
701 Veterans Circle
Warminster, Pennsylvania
United States , 18974
Country 94423 0
United States of America
Phone 94423 0
+1 267 469 0914
Fax 94423 0
Email 94423 0
clinicaltrials@arbutusbio.com
Contact person for scientific queries
Name 94424 0
Mr Michael Child
Address 94424 0
Arbutus Biopharma Corporation,
701 Veterans Circle
Warminster, Pennsylvania
United States , 18974
Country 94424 0
United States of America
Phone 94424 0
+1 267 469 0914
Fax 94424 0
Email 94424 0
clinicaltrials@arbutusbio.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Not Applicable


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.