Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000317796
Ethics application status
Approved
Date submitted
14/12/2021
Date registered
21/02/2022
Date last updated
23/08/2024
Date data sharing statement initially provided
21/02/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Study Investigating the Safety and Immunogenicity of AB-729 and VTP 300 in Virologically Suppressed CHB Participants
Scientific title
A Phase 2a, Randomized, Blinded, Multicenter Study Investigating a Combination of AB-729 and VTP-300 to evaluate their safety and reactogenicity in Virologically-Suppressed Chronic Hepatitis B Participants.
Secondary ID [1] 305886 0
AB-729-202
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Virologically-Suppressed Chronic Hepatitis B 324436 0
Condition category
Condition code
Infection 321928 321928 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
AB-729 is a GalNAc-conjugated siRNA inhibitor of hepatitis B virus (HBV). VTP-300 is an HBV-specific therapeutic vaccine that uses a prime-boost platform of ChAdOx1-HBV followed by MVA-HBV. Forty participants who are stably virally suppressed on oral tablet nucleos(t)ide analogue (NA) therapy [Tenofovir Disoproxil (TDF), Tenofovir Alafenamide (TAF) or Entecavir (ETV) will receive 60 mg of AB-729 subcutaneously every 8 weeks (Q8W) for the first 24 weeks plus NA daily. At Week 24 participants will be randomized 1:1 to one of 2 groups (Group A or B) to receive VTP-300 (intramuscular [IM] administration ChAdOx1-HBV (2.5 x 10¹°vp) at Week 26, followed by one dose of IM MVA-HBV [1 x 10 (power 8) pfu] at Week 30 or placebo plus NA.

Randomization into Group A or Group B will be stratified by HBsAg level.

Participants who experience a pre-determined decline in HBsAg from Week 26 to Week 34 will receive a second dose of IM MVA-HBV at Week 38. Participants, investigators and site staff performing safety assessments are blinded to the VTP-300. AB-729 and VTP-300 will be administered in the clinic only. Adherence will be monitored via clinical site staff recording and reporting administration of IP (AB-729 and VTP-300) and by subject dosing diary and tablet reconciliation at the site (NAs).

At Week 48, all participants will be evaluated for eligibility to discontinue NA therapy based on levels of ALT, HBV DNA, HBeAg and HBsAg. Otherwise they will remain on their NA therapy.

Participants who discontinue their NA will be followed for an additional 48 weeks. Participants who do not discontinue their NA will be followed for an additional 24 weeks

After the first 40 participants have been allocated to Groups A or B, screening may proceed for Group C with aim to enrol 20 participants. Group C will be open label where all enrolled participants will receive AB-729 60 mg every 8 weeks + NA for 24 weeks and then receive a course of VTP-300 + nivolumab (ChAdOx1-HBV at Week 26, MVA-HBV + nivolumab (0.3 mg/kg via intravenous infusion) at Week 30. If a participant’s HBsAg at Week 34 is greater than or equal to 10IU/mL, the participant will receive a second dose, if eligible, of MVA-HBV + nivolumab at Week 38. Participants will remain on their NA therapy throughout the VTP-300administration period through Week 48.
At Week 48 all participants will be evaluated for eligibility to either discontinue or remain on
their NA treatment. Participants who discontinue their NA will be followed for an additional 48 weeks to monitor for safety and evidence of clinical or virologic relapse. Participants who do not discontinue their NA will be followed for an additional 24 weeks.

This additional arm (Group C) was included that will assess if the addition of low dose nivolumab (0.3 mg/kg, one tenth the dose approved for oncologic indications) to the MVA-HBV boost component of VTP-300 will further stimulate reduction of HBsAg after initial treatment with AB-729 followed by the ChAdOx1-HBV prime.
Intervention code [1] 322289 0
Treatment: Drugs
Comparator / control treatment
Group and Group B - VTP-300 placebo: 0.9% sterile saline for injection
Route of administration: intramuscular injection.

Group C is open-label, as such there is no new placebo control group for Group C, but Group B may serve as a control for the addition of nivolumab to the VTP-300 regimen.
Control group
Placebo

Outcomes
Primary outcome [1] 329696 0
To evaluate the safety and reactogenicity of AB-729 followed by VTP-300 or placebo assessed by eDiary prompts and open-ended and non leading verbal questions, physical examinations, vital signs, ECG and clinical laboratory assessments (blood counts, chemistry, etc.).
Vital signs like blood pressure and heart measurements will be assessed by automated device while the participant is in seated or supine position. Same position must be used at every visit.
Timepoint [1] 329696 0
Treatment Emergent Adverse Events and Lab tests will be collected every 2-12 weeks from baseline to follow up (96 weeks)
Secondary outcome [1] 403484 0
To determine the effect of AB-729 followed by VTP-300 or placebo on levels of HBsAg and other viral markers as assessed by change in level of HBsAg and other viral markers

Other viral markers include HBV DNA, HBV RNA, hepatitis B virus core-related antigen (HBcrAg), hepatitis B virus surface antibody (HBsAb), and hepatitis B virus e-antigen/hepatitis B virus e-antibody (HBeAg/HBeAb) which are assessed by blood test.
Timepoint [1] 403484 0
Blood tests will be collected every 2-12 weeks from baseline to follow up (96 weeks)
Secondary outcome [2] 403487 0
To determine the proportion of participants who meet protocol defined NA treatment discontinuation by the ALT, HBeAg, HBV DNA and HBsAg levels at Week 48 via blood tests.
Timepoint [2] 403487 0
Week 48 (end of study treatment)
Secondary outcome [3] 403488 0
To determine the proportion of participants who maintain virologic control during the follow-up period
• Proportion of participants with HBV DNA less than Low limit of quantification (LLOQ) as assessed by via blood test
Timepoint [3] 403488 0
From Week 50 to 96 (Post treatment follow up period)
Secondary outcome [4] 403489 0
To determine the proportion of participants who experience clinical and/or viral relapse in the follow-up period after discontinuing NA therapy.
• Proportion of participants who discontinue NA therapy and subsequently meet protocol-defined clinical relapse criteria as assessed by blood tests and audit of study database,
Timepoint [4] 403489 0
From Week 50 to 96 (Post treatment follow up period)
Secondary outcome [5] 403490 0
Assess the HBV specific cellular immune response generated by AB-729 followed by VTP-300 or placebo total T cell interferon-gamma (IFN-gamma) production induced by the regimens as measured by IFN-gamma ELISpot
Timepoint [5] 403490 0
Tests for IFN- gamma ELISpot will be collected every 2 – 12 weeks from baseline to follow up (96 weeks)
Secondary outcome [6] 403491 0
To characterize the pharmacokinetics (PK) of AB-729 followed by VTP-300 or placebo
Pharmacokinetics parameter includes
Cmax: Maximum observed plasma concentration
Tmax: Time of maximum observed plasma concentration
AUC0-t: Area under the concentration time- curve from the time of dosing to the last measurable concentration
Timepoint [6] 403491 0
Plasma sample collected from all participants at Day 1 (predose, 0.5 hours, 1 hours, 2 hours, 4 hours, 6 hours) and Week 24 (predose, 0.5 hours, 1 hours, 2 hours, 4 hours, 6 hours)
Secondary outcome [7] 405677 0
To determine the proportion of participants who experience clinical and/or viral relapse in the follow-up period after discontinuing NA therapy.

• Proportion of participants who discontinue NA therapy and subsequently meet protocol-defined viral relapse criteria as assessed by blood tests and audit of study database
Timepoint [7] 405677 0
From week 50 to 96 (Post treatment follow up period)
Secondary outcome [8] 406124 0
To determine the proportion of participants who maintain virologic control during the follow-up period
• Proportion of participants who restart NA therapy during the follow-up period via audit of study database
Timepoint [8] 406124 0
From week 50 to 96 (Post treatment follow up period)

Eligibility
Key inclusion criteria
1. Adult male or female participants, 18 to 65 years of age, inclusive.
2. Male and female participants are eligible if they agree to use protocol-defined contraception
3. Body mass index (BMI) greater than 18 kg/m2 and less than 35 kg/m2.
4. Documented chronic HBV infection: positive HBsAg, HBV DNA, or HBeAg at least 6 months prior to the Screening Visit (historical documentation must be provided) and negative serum immunoglobulin M (IgM) anti-hepatitis B core-related antibody (HBcAb) at the Screening Visit
5. Participants must have HBV DNA less than 20 IU/mL at screening and have been receiving either TAF, TDF, or ETV consistently for greater than 12 months prior to Day 1 and are willing to continue with the same NA treatment through the final study visit..
6. HBsAg greater than 100 IU/ml and less than 5,000 IU/mL at Screening.
7. All participants must have assessment of fibrosis demonstrating non-cirrhotic status.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Known co-infection with HIV, hepatitis A, C, D, or E
2. Any known preexisting medical or psychiatric condition that could interfere with the participant’s ability to provide informed consent or participate in study conduct, or that may confound study findings
3. History of any clinically significant medical condition associated with chronic liver disease, evidence of decompensated liver disease, findings suggestive of hepatocellular carcinoma (HCC) at any time. or cirrhosis at any time
4. Immunologically mediated disease or significant immunosuppression from disease or medication.
5. Any known or suspected hypersensitivity, anaphylactic reactions or previous severe reactions to any of the constituents of AB-729 or VTP-300.
6. ALT greater than 2 × ULN of the laboratory reference range.
7. Direct or total bilirubin greater than 1.5 × ULN of the laboratory reference range.

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)
The allocation procedure is per an central randomisation by computer for group A and B. This does not apply to group C
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomization schedule will be generated by the clinical contract research organization (CRO) or study statistician and retained for the study. Interactive Response Technology (IRT) system will be used for treatment allocation and randomization for group A and Group B. This does not apply to group C
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Other
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
28/02/2022
Actual
2/06/2022
Date of last participant enrolment
Anticipated
31/08/2022
Actual
20/11/2023
Date of last data collection
Anticipated
13/09/2025
Actual
Sample size
Target
62
Accrual to date
Final
62
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 21225 0
The Alfred - Melbourne
Recruitment postcode(s) [1] 36094 0
3004 - Melbourne
Recruitment outside Australia
Country [1] 24350 0
Taiwan, Province Of China
State/province [1] 24350 0
Kaohsiung City
Country [2] 26523 0
Hong Kong
State/province [2] 26523 0
United Kingdom

Funding & Sponsors
Funding source category [1] 310236 0
Commercial sector/Industry
Name [1] 310236 0
Arbutus Biopharma
Country [1] 310236 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Arbutus Biopharma
Address
701 Veterans Circle
Warminster, PA 18974
Country
United States of America
Secondary sponsor category [1] 311331 0
Commercial sector/Industry
Name [1] 311331 0
Vaccitech Ltd
Address [1] 311331 0
The Oxford Science Park, Heatley Rd, Oxford OX4 4GE
Country [1] 311331 0
United Kingdom
Other collaborator category [1] 282079 0
Commercial sector/Industry
Name [1] 282079 0
Novotech (Australia) Pty Limited
Address [1] 282079 0
Level 3, 235 Pyrmont Street, Pyrmont NSW 2009
Country [1] 282079 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309915 0
St Vincent's Hospital Melbourne Human Research Ethics Committee
Ethics committee address [1] 309915 0
Ethics committee country [1] 309915 0
Australia
Date submitted for ethics approval [1] 309915 0
29/10/2021
Approval date [1] 309915 0
17/12/2021
Ethics approval number [1] 309915 0
Project ID Number: 81044 St Vincent’s HREC Ref: HREC 280/21

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

Contacts
Principal investigator
Name 115818 0
Prof Prof. Stuart Keith Roberts
Address 115818 0
Gastroenterology Department Alfred Hospital
55 Commercial Road
Melbourne, VIC Australia 3004
Country 115818 0
Australia
Phone 115818 0
+61 03 9076 3375
Fax 115818 0
+61 03 9076 2194
Email 115818 0
[email protected]
Contact person for public queries
Name 115819 0
Deana Antoniello
Address 115819 0
Arbutus Biopharma
701 Veterans Circle Warminster, PA 18974
Country 115819 0
United States of America
Phone 115819 0
+442673327188
Fax 115819 0
Email 115819 0
[email protected]
Contact person for scientific queries
Name 115820 0
Karen Sims
Address 115820 0
Arbutus Biopharma
701 Veterans Circle Warminster, PA 18974
Country 115820 0
United States of America
Phone 115820 0
+442673329255
Fax 115820 0
Email 115820 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


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.