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Trial registered on ANZCTR


Registration number
ACTRN12618001438246
Ethics application status
Approved
Date submitted
17/08/2018
Date registered
28/08/2018
Date last updated
12/11/2018
Date data sharing statement initially provided
9/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Study to investigate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AB-452 in Healthy Subjects and Subjects with Chronic HBV Infection
Scientific title
A Double-Blind, Randomized, Placebo-Controlled, Single and Multiple Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AB-452 Following Oral Administration in Healthy Subjects and Subjects with Chronic Hepatitis B
Secondary ID [1] 295770 0
AB-452-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic HBV Infection 309171 0
Condition category
Condition code
Infection 308048 308048 0 0
Other infectious diseases
Oral and Gastrointestinal 308049 308049 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 2 parts. The first part will be conducted in approximately 28 healthy subjects. The second part will be conducted in approximately 48 CHB subjects.
Part 1 SAD(Cohorts A and B): Subjects will receive single ascending doses of AB-452 or placebo administered orally. The starting dose will be 30 mg. Subsequent doses in Part 1, will be confirmed after review of safety, tolerability and PK data from prior dose levels. The maximum dose of AB-452 for Part 1 will be no more than 800 mg. Subjects in one of the dosing cohorts (in Cohort A) will be administered single oral dose of AB-452, 2 hours after single oral dose of ranitidine 150mg under fasted conditions.
Part 1 MD (Multiple Dose) (Cohort C): Subjects will receive AB-452 or placebo once or twice daily for up to 7 days, administered orally. The dose of AB-452 will be based upon Part 1, SAD.
Part 2: CHB Subjects will receive AB-452 or placebo once or twice daily for 28 days, administered orally. The starting dose in Part 2 will not exceed the dose tested in Part 1, MD panel, and subsequent doses in Part 2 will be confirmed after review of safety, virologic and PK data from prior dose levels.

Part 1: Subjects will take their study medication in the presence of study staff. Compliance will be confirmed by a mouth check after dosing.
Part 2: 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.
In the Part 1 MD panel, all subjects will receive AB-452 once daily or all subjects will receive twice daily dosing. Dosing frequency will be based on Part 1 SAD. The initial dosing frequency in Part 2 (Cohort D) will be based on Part 1 (SAD and MD panels), while the dosing frequency in Cohorts E and F will be based on the totality of data available at that point (SAD, MD, and Cohort D).
Intervention code [1] 312097 0
Treatment: Drugs
Comparator / control treatment
Matching placebo (Microcrystalline cellulose capsule) administered orally for AB-452 will be used for the study.
Control group
Placebo

Outcomes
Primary outcome [1] 307065 0
To evaluate the safety and tolerability of AB-452 following oral administration of single and multiple doses (up to 28 days) to healthy subjects and 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-452.
Timepoint [1] 307065 0
Part 1 SAD:
Monitored daily through Day 4 and then at Day 7 after the last dose of study treatment for each treatment period.
Part 1 MD:
Monitored daily through Day 10 and then at Day 18 (11 days after the last dose of study treatment).
Part 2:
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] 350516 0
Pharmacokinetics (PK) parameters (Cmax, Tmax, AUC, Ctrough) of AB-452 following administration of AB-452.
Timepoint [1] 350516 0
Part 1 SAD: Blood and Urine for PK will be collected at Day 1 of AB-452 dosing and Day 2, Day 3, Day 4 of post-dosing period.
Part 1 MD: Blood for PK will be collected at Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, and Day 7 of AB-452 dosing and at Day 8, Day 9, and Day 10 of post-dosing period.
Part 2 CHB : Blood samples for PK will be collected at Day 1, Day 3, Day 7, Day 14, Day 21, Day 28 of AB-452 dosing.
Secondary outcome [2] 350517 0
Part 2: To evaluate the change in HBsAg in CHB subjects over 28 days of dosing of AB-452. Serum assay tests will be used.
Timepoint [2] 350517 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.
Secondary outcome [3] 351004 0
Cohort G only, proportion of subjects with a change in HBV-DNA meeting response criteria (Greater than or equal to 0.5, 1, 2, or 3 log10 reduction; Less than or equal to LLOQ)
Timepoint [3] 351004 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 (SAD and MD- Healthy Subjects)
- 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 2 (CHB Subjects)
- Adult male or female subjects, 18 to 65 years of age, inclusive.
- 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.
- Quantitative HBsAg >/=1000 IU/mL at the Screening Visit.
- Subjects must be HBeAg-negative or HBeAg-positive at least 3 months prior to the Screening Visit.
- Subjects must be either treatment naive or on-treatment
- Liver ultrasound with absence of clinically significant abnormalities is required < /=6 months prior to Day 1.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion Criteria for Study Part 1 (SAD and MD- Healthy Subjects)
Medical Status or History
- A history of clinically significant gastrointestinal, hematologic, renal, hepatic, bronchopulmonary, neurological, psychiatric, or cardiovascular disease, Gilbert’s Syndrome.
- Positive pregnancy test at Screening or Day -1.

Findings/Diagnostic Assessments
- Clinically significant ECG or vital sign abnormalities at Screening, Day -1, and Day 1 pre-dose.
- Clinically significant abnormalities in laboratory test results at Screening or Day -1 that are confirmed by a repeat reading.

Exclusion Criteria for Study Part 2 (CHB Subjects)
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. Active/acute 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, or hepatic encephalopathy.
c. Liver ultrasound or other imaging with findings suggestive of HCC.
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 < /=1 week prior to the first dose of study treatment.

Findings/Diagnostic Assessments at Screening, Confirmed by Repeat Testing
- QTc interval >450 msec for males or >470 msec for females at Screening or baseline (Day 1) visit.
- Total bilirubin >1.5 × upper limit of normal.

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 CHB subjects) across the study.

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
Initiation of the trial has been delayed to devote additional time to further characterize the compound before potentially initiating clinical trials.
Date of first participant enrolment
Anticipated
8/10/2018
Actual
Date of last participant enrolment
Anticipated
21/08/2019
Actual
Date of last data collection
Anticipated
15/10/2019
Actual
Sample size
Target
76
Accrual to date
Final
Recruitment outside Australia
Country [1] 20742 0
Hong Kong
State/province [1] 20742 0
Country [2] 20743 0
Korea, Republic Of
State/province [2] 20743 0
Country [3] 20744 0
United Kingdom
State/province [3] 20744 0
Country [4] 20745 0
Romania
State/province [4] 20745 0
Country [5] 20746 0
New Zealand
State/province [5] 20746 0
Auckland
Country [6] 20747 0
Singapore
State/province [6] 20747 0

Funding & Sponsors
Funding source category [1] 300358 0
Commercial sector/Industry
Name [1] 300358 0
Arbutus Biopharma Corporation
Country [1] 300358 0
Canada
Primary sponsor type
Commercial sector/Industry
Name
Arbutus Biopharma Corporation
Address
100 – 8900 Glenlyon Parkway
Burnaby, British Columbia
Canada V5J 5J8
Country
Canada
Secondary sponsor category [1] 299802 0
None
Name [1] 299802 0
Address [1] 299802 0
Country [1] 299802 0
Other collaborator category [1] 280295 0
Commercial sector/Industry
Name [1] 280295 0
Novotech (Australia) Pty Limited
Address [1] 280295 0
Level 3, 235 Pyrmont Street, Pyrmont NSW 2009
Country [1] 280295 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301172 0
Northern A Health and Disability Ethics Committee
Ethics committee address [1] 301172 0
Novotel Ellerslie, 72-112 Greenlane Rd East, Ellerslie, Auckland 1051, New Zealand,
Ethics committee country [1] 301172 0
New Zealand
Date submitted for ethics approval [1] 301172 0
08/08/2018
Approval date [1] 301172 0
17/09/2018
Ethics approval number [1] 301172 0

Summary
Brief summary
The study drug AB-452 is being developed as a potential new treatment for Chronic Hepatitis B (CHB). The main goal of the study is to determine whether AB-452 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.
The study drug AB-452 is being developed as a potential new treatment for Chronic Hepatitis B (CHB). The main goal of the study is to determine whether AB-452 is safe and well tolerated. The study consists of two parts. In Part 1, healthy subjects will receive single or multiple increasing doses of AB-452. In Part 2, CHB subjects will receive multiple increasing doses of AB-452.

Part 1 SAD(Cohorts A and B): Subjects will receive single ascending doses of AB-452 or placebo administered orally. The starting dose will be 30 mg. Subsequent doses in Part 1, will be confirmed after review of safety, tolerability and PK data from prior dose levels. The maximum dose of AB-452 for Part 1 will be no more than 800 mg. Subjects in one of the dosing cohorts (in Cohort A) will be administered single oral dose of AB-452, 2 hours after single oral dose of ranitidine 150mg under fasted conditions.
Part 1 MD (Multiple Dose) (Cohort C): Subjects will receive AB-452 or placebo once or twice daily for up to 7 days, administered orally. The dose of AB-452 will be based upon Part 1, SAD.
Part 2: CHB Subjects will receive AB-452 or placebo once or twice daily for 28 days, administered orally. The starting dose in Part 2 will not exceed the dose tested in Part 1, MD panel, and subsequent doses in Part 2 will be confirmed after review of safety, virologic and PK data from prior dose levels.

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 86094 0
Prof Edward Gane
Address 86094 0
Auckland Clinical Studies Ltd and Auckland City Hospital, PO Box 8963, Symonds St, Auckland, 1150
Country 86094 0
New Zealand
Phone 86094 0
+64 21 548 371
Fax 86094 0
Email 86094 0
EdGane@adhb.govt.nz
Contact person for public queries
Name 86095 0
Jill M. Denning
Address 86095 0
Arbutus Biopharma Corporation, 701 Veterans Circle, Warminster, Pennsylvania, United States 18974
Country 86095 0
United States of America
Phone 86095 0
+1 267 469 0914
Fax 86095 0
Email 86095 0
clinicaltrials@arbutusbio.com
Contact person for scientific queries
Name 86096 0
Jill M. Denning
Address 86096 0
Arbutus Biopharma Corporation, 701 Veterans Circle, Warminster, Pennsylvania, United States 18974
Country 86096 0
United States of America
Phone 86096 0
+1 267 469 0914
Fax 86096 0
Email 86096 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


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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No additional documents have been identified.