Maternal Antiviral Prophylaxis to Prevent Perinatal Transmission of Hepatitis B Virus in Thailand (iTAP)

February 12, 2021 updated by: GONZAGUE JOURDAIN, Institut de Recherche pour le Developpement

Phase 3, Randomized Clinical Trial to Assess the Efficacy and Safety of Tenofovir in Hepatitis B Virus Infected, s and e Antigen Positive, Pregnant Women to Prevent Perinatal Transmission Despite Infant Passive-active HBV Immunization.

Chronic hepatitis B (CHB) infection is complicated by cirrhosis and liver cancer. In Thailand, 7% of adults are chronically infected by Hepatitis B virus (HBV). The risk of perinatal transmission of HBV is about 12% when a mother has a high HBV load in her plasma, even if her infant receive specific immunoglobulin and vaccine.

The hypothesis of this study is that a potent antiviral, tenofovir, can decrease HBV load in HBV infected pregnant women and therefore reduce the risk of perinatal transmission/ Pregnant women participating in this study will receive tenofovir or placebo during the last trimester of pregnancy and two months postpartum. The risk of perinatal transmission will be compared between the two groups.

The results of the study will help define policy to manage HBV infected pregnant women to prevent perinatal transmission.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

This is a phase III, placebo controlled, double blind, randomized clinical trial to assess the efficacy and safety of tenofovir disoproxil fumarate (TDF) given from 28 weeks' gestation until 2 months postpartum to pregnant women with Hepatitis B (HB) virus (HBV) chronic infection and positive for HB s and e antigen to prevent perinatal transmission of HBV to their infants. All infants will receive HBV passive (HB specific immunoglobulin) and active (vaccine) immunization.

Chronic hepatitis B (CHB) infection is complicated by cirrhosis and hepatocellular carcinoma (HCC), the 10th leading cause of death worldwide.

In 2011, about 7% of adults in Thailand were HBsAg carriers. Infant hepatitis B (HB) immunization and HB immune globulin (HBIg) administered at birth effectively prevent most mother-to-child transmission (MTCT) of HBV. However, about 12% of mothers with high load of HBV transmit the virus to their infants, despite active and passive immunization.

Studies have suggested that antiviral treatment at the end of pregnancy and during early postpartum can reduce the risk of transmission to the child. A potential limitation to this approach is the risk of hepatic disease exacerbation following discontinuation of antiviral treatment postpartum, and this risk has not been properly evaluated. No randomized clinical trials have adequately demonstrated the efficacy and safety of maternal antiviral treatment the prevention of mother to child transmission of HBV. This is the reason why this approach is not currently recommended by the Associations for the Study of Liver Diseases.

We hypothesize that a potent antiviral, tenofovir, can decrease HBV viral load in HBV infected pregnant women and therefore reduce the risk of perinatal transmission, before infants are definitely protected by passive-active immunization. We also hypothesize that only moderate exacerbations of liver disease will be observed after discontinuation of a short antiviral course (5 months). While the primary objective of the study is to assess the efficacy of tenofovir versus placebo for the prevention of perinatal transmission, an important secondary objective is the assessment of the risk of postpartum hepatic disease exacerbation.

Within 2 years, 328 women and their infants will be enrolled from public hospitals in Thailand and randomized to receive either tenofovir disoproxil fumarate or matching placebo from 28 weeks of pregnancy until 2 months postpartum. Mothers and infants will be followed until one year postpartum.

The primary endpoint will be the detection of HBsAg and HBV DNA in infants at six months of life. An interim analysis will be conducted when half of the outcomes are available.

Study Type

Interventional

Enrollment (Actual)

654

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Thailand
      • Bangkok, Thailand, 10220
        • Bhumibol Adulyadej Hospital
      • Bangkok, Thailand, 10230
        • Nopparat Rajathanee Hospital
      • Chanthaburi, Thailand, 22000
        • Prapokklao Hospital
      • Chiang Mai, Thailand, 50180
        • Nakornping Hospital
      • Chiang Mai, Thailand, 50100
        • Health Promotion Center Region 10
      • Chiang Rai, Thailand, 57000
        • Chiangrai Prachanukroh Hospital
      • Chon Buri, Thailand, 20000
        • Chonburi Regional Hospital
      • Khon Kaen, Thailand, 40000
        • Khon Kaen hospital
      • Lampang, Thailand, 52000
        • Lampang Hospital
      • Lamphun, Thailand, 51000
        • Lamphun Hospital
      • Phayao, Thailand, 56000
        • Phayao Provincial Hospital
      • Samut Prakan, Thailand, 10280
        • Samutprakarn Hospital
      • Samut Sakhon, Thailand, 74000
        • Samutsakhon Hospital
    • Chiangrai
      • Mae Chan, Chiangrai, Thailand, 57110
        • Mae Chan Hospital
    • Chon Buri
      • Bang Lamung, Chon Buri, Thailand, 20150
        • Banglamung Hospital
    • Nakhon Ratchasrima
      • Nakhon Ratchasima, Nakhon Ratchasrima, Thailand, 30000
        • Maharat Nakhon Ratchasima Hospital
    • Phayao
      • Chiang Kham, Phayao, Thailand, 56110
        • Chiang Kham Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Pregnancy
  • At least 18 years of age
  • Negative Human Immunodeficiency Virus (HIV) serology
  • Positive HBsAg and hepatitis B e antigen (HBeAg) tests
  • Gestational age of 28 weeks (+ or - 10 days) as determined by obstetrician
  • Alanine Aminotransferase (ALT)≤30 U/L, confirmed ≤60 U/L on a subsequent blood draw
  • Agreeing to bring their infants at the planned study visits at one study site until one year after delivery and to inform the site investigators if they plan to move to another place and not be able to return to the clinic.
  • Understanding the need for adequate infant immunization and agreeing to the blood draws from their infants and the need for close follow up to manage possible exacerbation of hepatitis.

Exclusion Criteria:

  • History of tenofovir treatment at any time, or any other anti-HBV treatment during the current pregnancy
  • Creatinine clearance <50 ml/min, calculated using the Cockcroft-Gault formula
  • Dipstick proteinuria>1+ (>30 mg/dL) or normoglycemic glucosuria confirmed on two separate occasions
  • Positive serology for Hepatitis C infection less than 12 months prior to enrollment
  • Evidence of pre-existing fetal anomalies incompatible with life
  • Any concomitant condition or treatment that, in the view of the clinical site investigator, would contraindicate participation or satisfactory follow up in the study.
  • Concurrent participation in any other clinical trial without written agreement of the two study teams

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: PREVENTION
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: QUADRUPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Tenofovir disoproxil fumarate
tenofovir disoproxil fumarate, 300 mg tablets
Drug: tenofovir disoproxil fumarate
administration: tablet 300 mg, once a day, from enrollment at 28 weeks' gestation until 2 months postpartum
Other Names:
  • TDF
  • Viread
  • tenofovir
PLACEBO_COMPARATOR: Placebo
matching placebo (of tenofovir disoproxil fumarate)
Drug: placebo
administration: one tablet, once a day, from enrollment at 28 weeks' gestation until 2 months postpartum

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Infants With Hepatitis B Infection at 6 Months of Age
Time Frame: 6 months of age
Infection is defined as a HBsAg positive test confirmed by detectable HBV DNA
6 months of age

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Participants With Adverse Events
Time Frame: from enrollment (28 weeks' gestation) to 12 months postpartum
Occurrence of maternal and infant adverse events, including maternal and infants Serious Adverse Events (as defined by the International Conference on Harmonization Good Clinical Practice) and NIH Division of AIDS grade 3/4 signs and symptoms, regardless of their relatedness to the study treatment.
from enrollment (28 weeks' gestation) to 12 months postpartum
Percentage of Participants With Flares After Study Treatment Interruption
Time Frame: Following planned discontinuation of study treatment up to 12 months postpartum
Flare, or acute exacerbation of hepatitis B, after study treatment interruption is defined as an Alanine Aminotransferase plasma level above 300 IU/mL
Following planned discontinuation of study treatment up to 12 months postpartum
Percentage of Infants With Hepatitis B Infection at or After 6 Months Through 12 Months of Age
Time Frame: at or after 6 months through 12 months of age
Infants will be considered HBV infected if at any time point at or after 6 months through 12 months of age, a sample tests positive for HBsAg and HBV DNA
at or after 6 months through 12 months of age
Weight, Height and Head Circumference for Age
Time Frame: assessed at 6 months and 12 months of age, 6 months reported
Weight, length/height and head circumference WHO Z scores are measures of relative weight, height and head circumference adjusted for child age and sex. The Z-score indicates the number of standard deviations away from a reference population in the same age range and with the same sex. A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean.
assessed at 6 months and 12 months of age, 6 months reported

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Institut de Recherche pour le Developpement

Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Gilead Sciences
Centers for Disease Control and Prevention

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2013

Primary Completion (ACTUAL)

December 1, 2016

Study Completion (ACTUAL)

October 1, 2018

Study Registration Dates

First Submitted

December 6, 2012

First Submitted That Met QC Criteria

December 7, 2012

First Posted (ESTIMATE)

December 10, 2012

Study Record Updates

Last Update Posted (ACTUAL)

March 5, 2021

Last Update Submitted That Met QC Criteria

February 12, 2021

Last Verified

February 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • U01HD071889 (NIH)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

Pending completion of analysis planned in the protocol

Study Data/Documents

  1. Individual Participant Data Set

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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