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Trial registered on ANZCTR


Registration number
ACTRN12623001202651p
Ethics application status
Submitted, not yet approved
Date submitted
26/10/2023
Date registered
21/11/2023
Date last updated
21/11/2023
Date data sharing statement initially provided
21/11/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Field trial to assess the effectiveness of treating-all pregnant women with hepatitis B with tenofovir to reduce the incidence of hepatitis B in infants 6-12 months after birth
Scientific title
Field trial in Vanuatu to assess the effectivess of treating-all pregnant women with hepatitis B with tenofovir prophylaxis to prevent mother-to-child transmission compared to guideline-based care
Secondary ID [1] 310810 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
hepatitis B 331801 0
Condition category
Condition code
Infection 328537 328537 0 0
Other infectious diseases
Oral and Gastrointestinal 328683 328683 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 intervention is a variation of the World Health Organization (WHO) 2020 Guidelines on Antiviral Prophylaxis in Pregnancy. All hepatitis B surface antigen (HBsAg)-positive pregnant women allocated to the treat-all arm will be provided with tenofovir prophylaxis (without treatment eligibility based on HBV DNA level, as per the 2020 WHO Guidelines) .

Therapeutic: Tenofovir disoproxil fumarate (TDF). Tenofovir disoproxil fumarate was added to the Vanuatu Essential Medicines List in 2020 and is the only antiviral therapy for hepatitis B infection available in Vanuatu.
Route of administration: Oral
Dosage: 300 mg tablet to be ingested orally once daily.
Duration: Week 28 of pregnancy until at least 6 weeks after delivery.
Intervention code [1] 327224 0
Prevention
Intervention code [2] 327225 0
Treatment: Drugs
Comparator / control treatment
The control arm is implementation of the WHO 2020 Guidelines on Antiviral Prophylaxis in Pregnancy. The research nurse will refer HBsAg-positive mothers allocated to the control group to the high-risk pregnancy clinic for management during pregnancy.

Eligibility: In the guideline-based care arm, participants with HBV DNA level greater than or equal to 200,000 IU/mL will be eligible for treatment.
Therapeutic: TDF.
Route of administration: Oral
Dosage: 300 mg tablet to be ingested orally once daily.
Duration: Week 28 of pregnancy until at least 6 weeks after delivery.
Control group
Active

Outcomes
Primary outcome [1] 336359 0
Number and proportion of infants born to HBsAg-positive mothers that are HBsAg-positive
Timepoint [1] 336359 0
6-12 months post-birth.
Secondary outcome [1] 427998 0
Proportion of pregnant women in each trial arm that adhere to the antiviral prophylaxis in pregnancy regime from week 28 of pregnancy to delivery
Timepoint [1] 427998 0
At time of birth of the infant
Secondary outcome [2] 427999 0
Number and proportion of HBsAg-pregnant women that attended four ANC visits at the high-risk pregnancy clinic
Timepoint [2] 427999 0
At time of birth of the infant
Secondary outcome [3] 428000 0
Number and proportion of infants that were followed-up 6-12 months after delivery
Timepoint [3] 428000 0
6-12 months post-birth
Secondary outcome [4] 428001 0
Number and proportion of infants who received the hepatitis B birth dose
Timepoint [4] 428001 0
Within 24 hours of birth of the infant
Secondary outcome [5] 428002 0
The number of fetal deaths in each trial arm
Timepoint [5] 428002 0
Within 24 hours of birth of the infant
Secondary outcome [6] 428578 0
Number and proportion of infants who received the hepatitis B third dose
Timepoint [6] 428578 0
6-12 months post-birth
Secondary outcome [7] 428579 0
The number of pregnant women in each trial arm that experience post-partum hemorrhage
Timepoint [7] 428579 0
Within 24 hours of birth of the infant
Secondary outcome [8] 428580 0
The number of pregnant women in each trial arm that experience post-partum hepatic flare (defined as defined as elevated ALT levels to more than two times the upper limit of normal)
Timepoint [8] 428580 0
6 weeks after birth of the infant

Eligibility
Key inclusion criteria
Eligible participants include pregnant women aged 18 years and older, 14-28 weeks gestation at their first ANC appointment, that have a positive HBsAg test result during routine antenatal care, and able and willing to provide written informed consent prior to study-related procedures being performed. Infants born to eligible HBsAg-positive pregnant women are also considered participants.
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria includes women coinfected with either HIV or hepatitis C, evidence of cirrhosis or if already receiving hepatitis B antiviral therapy prior to pregnancy. Women not planning on delivering or living in Vanuatu in the 12 months after delivery (and therefore not available for follow-up) will also be excluded. Pregnant women with evidence of cirrhosis (indicated through calculation of the APRI score ([aspartate aminotransferase ratio index], which is calculated based on AST and platelet counts, as per the Vanuatu Hepatitis B Guidelines)) will be referred to separate clinics for hepatitis B treatment assessment but will not be eligible for inclusion in the study.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
For logistical purposes, allocation to control or intervention arms will be done in bulk. Block sampling will be used to ensure that groups are equal in size. Blocks sizes of five will be randomly allocated to the treat-all and guideline-based care arms until the required sample size is reached. The allocated intervention or control group will not be concealed.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
A total of 234 mother-infant pairs are required in each arm at the completion of the study (i.e. 117 mothers and their infants in each arm).

StataSE (v17) will be used for statistical analysis. Interim analysis will be conducted to determine the proportion of HBsAg-positive pregnant women enrolled in each arm that have high HBV DNA viral load to ensure that the sample size is sufficient. We anticipate that 35-40% of HBsAg-positive pregnant women will have high HBV DNA viral load (defined as HBV DNA level equal or greater than 200,000 IU/mL and interim analyses will be conducted at each increment of 50 participants recruited (that is, after 50, 100, 150, 200 participants). If there are insufficient numbers of HBsAg-positive pregnant women with a high HBV DNA viral load recruited, the required sample size will be recalculated.

Effect measures, comparing outcomes between intervention and control clusters, will be estimated with 95% confidence intervals and p-values from the corresponding hypothesis tests. The effect measure for the primary outcome measure will be a risk ratio, defined as the ratio between the proportion recorded as having the outcome of interest in the intervention arm, and the corresponding proportion in the control arm.

Primary data analysis will be by intention to treat, meaning that all participants with a recorded outcome will be included in the analysis, and will be analysed according to the treatment group to which they were allocated.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/03/2024
Actual
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
30/06/2025
Actual
Sample size
Target
234
Accrual to date
Final
Recruitment outside Australia
Country [1] 25907 0
Vanuatu
State/province [1] 25907 0

Funding & Sponsors
Funding source category [1] 315051 0
Charities/Societies/Foundations
Name [1] 315051 0
Thrasher Research Fund
Country [1] 315051 0
United States of America
Primary sponsor type
University
Name
Burnet Institute
Address
85 Commerical Road, Melbourne, Victoria, Australia, 3004
Country
Australia
Secondary sponsor category [1] 317074 0
None
Name [1] 317074 0
Address [1] 317074 0
Country [1] 317074 0
Other collaborator category [1] 282851 0
University
Name [1] 282851 0
Doherty Institute
Address [1] 282851 0
792 Elizabeth Street Melbourne, Victoria, Australia, 3000
Country [1] 282851 0
Australia
Other collaborator category [2] 282852 0
Government body
Name [2] 282852 0
Vanuaty Ministry of Health
Address [2] 282852 0
Iatka Complex, Port Vila, SHEFA Province, Vanuatu
Country [2] 282852 0
Vanuatu

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 314006 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 314006 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 314006 0
Australia
Date submitted for ethics approval [1] 314006 0
26/10/2023
Approval date [1] 314006 0
Ethics approval number [1] 314006 0

Summary
Brief summary
Recent WHO guidance for prevention of mother-to-child transmission (MTCT) of hepatitis B virus (HBV) recommends tenofovir prophylaxis during pregnancy for pregnant women with a high HBV DNA viral load, however there is limited access to laboratory testing in Pacific Island Countries (PIC). The objective of this study is to assess if providing all HBV-infected pregnant women with tenofovir prophylaxis is more effective in PIC than restricting tenofovir to those that can access laboratory testing. We hypothesize that providing all HBV-infected pregnant women with tenofovir prophylaxis will reduce the incidence of hepatitis B among infants born to HBV-infected mothers compared to only proving tenofovir prophylaxis to those with laboratory evidence of high hepatitis B DNA viral load.
This study is a two-arm parallel, block randomized field trial that compares the “treat-all” approach to “guideline-based care”. The study population includes HBV-infected pregnant women and their infant/s. The primary outcome measure is the proportion of HBV-infected infants at 6-12 months after birth.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 130098 0
Dr Caroline van Gemert
Address 130098 0
Burnet Institute, 85 Commercial Road, Melbourne, Victoria, 3004
Country 130098 0
Australia
Phone 130098 0
+61 423853930
Fax 130098 0
Email 130098 0
[email protected]
Contact person for public queries
Name 130099 0
Caroline van Gemert
Address 130099 0
Burnet Institute, 85 Commercial Road, Melbourne, Victoria, 3004
Country 130099 0
Australia
Phone 130099 0
+61 423853930
Fax 130099 0
Email 130099 0
[email protected]
Contact person for scientific queries
Name 130100 0
Caroline van Gemert
Address 130100 0
Burnet Institute, 85 Commercial Road, Melbourne, Victoria, 3004
Country 130100 0
Australia
Phone 130100 0
+61 423853930
Fax 130100 0
Email 130100 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?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
20751Study protocol    We will submit the protocol for publication in a p... [More Details]
20754Clinical study report    Results will be published by the investigators in ... [More Details]



Results publications and other study-related documents

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Documents added automatically
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