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Trial registered on ANZCTR


Registration number
ACTRN12618000987268
Ethics application status
Approved
Date submitted
4/06/2018
Date registered
13/06/2018
Date last updated
18/11/2019
Date data sharing statement initially provided
18/11/2019
Date results information initially provided
18/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A study to investigate the Safety, Tolerability, and Pharmacokinetics of AB-506 in Healthy Subjects and Subjects with Chronic HBV Infection
Scientific title
A Double-Blind, Randomized, Placebo-Controlled, Single and Multiple Dose Study Evaluating the Safety, Tolerability, and Pharmacokinetics of AB-506, an HBV Capsid Inhibitor, in Healthy Subjects and HBV-DNA Positive Subjects with Chronic HBV Infection
Secondary ID [1] 294739 0
AB-506-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic HBV Infection 307623 0
Condition category
Condition code
Infection 306769 306769 0 0
Other infectious diseases
Oral and Gastrointestinal 307318 307318 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. The first two parts will be conducted in approximately 28 healthy subjects. The third part will be conducted in approximately 48 CHB subjects.
Part 1: Subjects will receive single ascending doses of AB-506 or placebo administered orally. The starting dose will be 30 mg. Subsequent doses in Part 1 will be confirmed after review of safety and PK data from prior dose levels. The maximum dose of AB-506 for Part 1 will be no more than 1000 mg.
Part 2: Subjects will receive daily doses of AB-506 or placebo for up to 10 days, administered orally. The dose tested in Part 2 will not exceed the maximum dose tested in Part 1. There is no minimum dosing period planned, subjects will continue treatment for up to 10 days unless subject experiences any AE or meets study discontinuation criteria.
Part 3: Subjects will receive daily doses of AB-506 or placebo for 28 days, administered orally. The starting dose in Part 3 will not exceed the dose tested in Part 2, and subsequent doses in Part 3 will be confirmed after review of safety and PK data from prior dose levels. Subjects in one of the dosing cohorts will be administered AB-506 with tenofovir (as tenofovir disoproxil fumarate [TDF]), administered orally, as a 300 mg tablet once daily, for 28 days.
Parts 1 and 2: Subjects will take their study medication in the presence of study staff. Compliance will be confirmed by a mouth check after dosing.
Part 3: On days that study drug is taken in the clinic, compliance will be confirmed by a mouth check after dosing. The subject will be instructed to bring all unused study medication in the original containers to each treatment period visit, as well as any empty bottles. The dates and number of tablets dispensed and returned must be recorded on the drug accountability form maintained on-site.
Intervention code [1] 301108 0
Treatment: Drugs
Comparator / control treatment
Matching placebo (Microcrystalline cellulose tablet), administered orally, for AB-506 will be used for the study.
Control group
Placebo

Outcomes
Primary outcome [1] 305770 0
To evaluate the safety and tolerability of AB-506 following oral administration of single and multiple doses (up to 28 days) to healthy subjects and HBV-DNA+ subjects with CHB as assessed by the frequency and severity of treatment emergent adverse events (TEAEs), discontinuations due to adverse events (AEs), and laboratory abnormalities, by cohort, after single doses or multiple doses up to 28 days of dosing with AB-506.
Timepoint [1] 305770 0
Part 1:
Monitored daily through Day 4 and then at Day 14 after the last dose of study treatment for each treatment period.
Part 2:
Monitored daily through Day 13 and then at Day 21 (11 days after the last dose of study treatment).
Part 3:
Monitored on Day 3, Day 7, Day 14, Day 21 and Day 28, and 14 (Day 42) and 28 (Day 56) days after the last dose of study treatment.
Secondary outcome [1] 346468 0
Pharmacokinetics (PK) parameters (Cmax, Tmax, T1/2, AUC, Ctrough) of AB-506 following administration of AB-506.
Timepoint [1] 346468 0
Part 1 only: Blood and Urine for PK will be collected at Day 1 of AB-506 dosing and Day 2, Day 3, Day 4 of post-dosing period.
Part 2 only: Blood for PK will be collected at Day 1 of AB-506 dosing and Day 3, Day 5, Day 7, Day 8, Day 9 and Day 10 of post-dosing period.
Part 3 only: Blood samples for PK will be collected at Day 1, Day 3, Day 7, Day 14, Day 21, Day 28 of AB-506 dosing.
Secondary outcome [2] 346470 0
Part 3 only: To evaluate the change in HBV-DNA and other virologic parameters in HBV-DNA+ subjects with CHB over 28 days of dosing of AB-506. Serum assay tests will be used.
Timepoint [2] 346470 0
Monitored on Day 3, Day 7, Day 14, Day 21 and Day 28, and 14 (Day 42) and 28 (Day 56) days after the last dose of study treatment.

Eligibility
Key inclusion criteria
Inclusion Criteria for Study Part 1 (Healthy Subjects - SAD) and Part 2 (Healthy Subjects - MD)
- Healthy males or females not of childbearing potential aged 18–45, inclusive.
- Male subjects must agree to use contraception as detailed in the protocol.
- Body mass index (BMI) >/= 18 kg/m2 and < /= 32 kg/m2.

Inclusion Criteria for Study Part 3 (CHB MAD)
- Adult male or female subjects, 18 to 65 years of age,
- 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.
- Body mass index (BMI) >/= 18 kg/m2 and < /= 38 kg/m2.
- Documented chronic HBV infection
- HBV genotype A, B, C, or D at screening.
- Subjects must be either treatment-naïve or treatment-experienced (off-treatment)
- HBV-DNA >/= 2,000 IU/mL at screening for HBeAg-negative subjects and HBV-DNA >/= 20,000 IU/mL at screening for HBeAg-positive subjects.
- HBsAg >/= 250 IU/mL at screening.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion Criteria for Study Part 1 (Healthy Subjects - SAD) and Part 2 (Healthy Subjects - MD)
Medical Status or History:
- A history of clinically significant gastrointestinal, hematologic, renal, hepatic, bronchopulmonary, neurological, psychiatric, cardiovascular disease, or evidence of active or suspected malignancy, or a history of malignancy.

Findings/Diagnostic Assessments:
- Clinically significant ECG or vital sign abnormalities at Screening, Day -1, or Day 1 pre-dose.
- Clinically significant abnormalities in laboratory test results at Screening or Day -1 that are confirmed by a repeat reading.
- Positive serology for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV).

Exclusion Criteria for Study Part 3 (CHB MAD)
Medical Status or History:
- Known co-infection with any of the following:
a. Human immunodeficiency virus (HIV),
b. Hepatitis C virus (HCV),
c. Hepatitis D virus (HDV), OR
d. Hepatitis E virus (HEV).
- Any known pre-existing 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. Evidence of decompensated liver disease including, but not limited to, a history or presence of clinical ascites, bleeding esophageal varices, hepatorenal syndrome, and/or hepatic encephalopathy.
c. Liver ultrasound or other imaging with findings suggestive of hepatocellular carcinoma (HCC) at any time.
d. Current or history of any clinically significant cardiac abnormalities/dysfunction
e. Immune-mediated disease or immunosuppression
f. Psychiatric disease
g. Malignancy
h. Clinically unstable medical condition within 2 weeks prior to the first dose of study treatment.

Findings/Diagnostic Assessments at Screening, confirmed by repeat testing:
- ALT or aspartate aminotransferase (AST) >5 × upper limit of normal (ULN).
- Total bilirubin >1.5 × ULN.
- Alpha fetoprotein (AFP) >100 ng/mL. For subjects with AFP results of 50 to 100 ng/mL, historical documentation of a liver ultrasound, computed tomography scan, or magnetic resonance imaging scan performed within 3 months prior to the first dose of study treatment to rule out HCC or other malignancy or liver abnormality must be provided.

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

Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
No hypothesis will be formally tested in this study. Approximately 148 subjects will be screened to achieve approximately 76 evaluable subjects (28 healthy subjects and 48 HBV-DNA+ CHB subjects) across the study.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
Arbutus Biopharma decided to discontinue development of AB-506 as two cases of acute hepatitis were observed in the Phase 1a 28-day clinical trial in healthy volunteers (AB-506-003).
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 10382 0
New Zealand
State/province [1] 10382 0
Auckland
Country [2] 10399 0
Hong Kong
State/province [2] 10399 0
Country [3] 10400 0
Thailand
State/province [3] 10400 0
Country [4] 10401 0
Korea, Republic Of
State/province [4] 10401 0
Country [5] 10402 0
Moldova, Republic Of
State/province [5] 10402 0

Funding & Sponsors
Funding source category [1] 299347 0
Commercial sector/Industry
Name [1] 299347 0
Arbutus Biopharma Corporation
Address [1] 299347 0
701 Veterans Circle
Warminster, PA 18974
Country [1] 299347 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Arbutus Biopharma Corporation
Address
701 Veterans Circle
Warminster, PA 18974
Country
United States of America
Secondary sponsor category [1] 298764 0
None
Name [1] 298764 0
Address [1] 298764 0
Country [1] 298764 0
Other collaborator category [1] 280106 0
Commercial sector/Industry
Name [1] 280106 0
Novotech (Australia) Pty Limited
Address [1] 280106 0
Level 3,235 Pyrmont Street, Pyrmont NSW 2009
Country [1] 280106 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300253 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 300253 0
Room GN.6, Ground Floor, Ministry of Health, 133 Molesworth Street, Wellington, New Zealand. 6011
Ethics committee country [1] 300253 0
New Zealand
Date submitted for ethics approval [1] 300253 0
10/05/2018
Approval date [1] 300253 0
25/06/2018
Ethics approval number [1] 300253 0

Summary
Brief summary
The study drug AB-506 is being developed as a potential new treatment for Chronic Hepatitis B (CHB). The main goal of the study is to determine whether AB-506 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 and look at whether this is affected by food.

Part 1: Subjects will receive single ascending doses of AB-506 or placebo administered orally. The starting dose will be 30 mg. Subsequent doses in Part 1 will be confirmed after review of safety and PK data from prior dose levels.
Part 2: Subjects will receive daily doses of AB-506 or placebo for up to 10 days, administered orally. The dose tested in Part 2 will not exceed the maximum dose tested in Part 1.
Part 3: Subjects will receive daily doses of AB-506 or placebo for 28 days, administered orally. The starting dose in Part 3 will not exceed the dose tested in Part 2, and subsequent doses in Part 3 will be confirmed after review of safety and PK data from prior dose levels. Subjects in one of the dosing cohorts will be administered AB-506 with tenofovir (as tenofovir disoproxil fumarate [TDF]), administered orally, for 28 days.

This study will help find new methods of treatment for the patients with CHB.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 83058 0
Prof Edward Gane
Address 83058 0
Auckland Clinical Studies Ltd and Auckland City Hospital, PO Box 8963, Symonds St, Auckland, 1150
Country 83058 0
New Zealand
Phone 83058 0
+64 21 548 371
Fax 83058 0
Email 83058 0
EdGane@adhb.govt.nz
Contact person for public queries
Name 83059 0
Mr Arbutus Clinical Development
Address 83059 0
Arbutus Biopharma Corporation
701 Veterans Circle
Warminster, Pennsylvania
United States 18974
Country 83059 0
United States of America
Phone 83059 0
+1 267 469 0914
Fax 83059 0
Email 83059 0
clinicaltrials@arbutusbio.com
Contact person for scientific queries
Name 83060 0
Mr Arbutus Clinical Development
Address 83060 0
Arbutus Biopharma Corporation
701 Veterans Circle
Warminster, Pennsylvania
United States 18974
Country 83060 0
United States of America
Phone 83060 0
+1 267 469 0914
Fax 83060 0
Email 83060 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 other documents available
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary