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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01745822
Recruitment Status : Completed
First Posted : December 10, 2012
Last Update Posted : June 14, 2019
Sponsor:
Collaborators:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Centers for Disease Control and Prevention
Gilead Sciences
Information provided by (Responsible Party):
GONZAGUE JOURDAIN, Institut de Recherche pour le Developpement

Tracking Information
First Submitted Date  ICMJE December 6, 2012
First Posted Date  ICMJE December 10, 2012
Last Update Posted Date June 14, 2019
Study Start Date  ICMJE January 2013
Actual Primary Completion Date December 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 11, 2018)
Infant's Hepatitis B infection status at 6 months of age [ Time Frame: 6 months of age ]
Infection is defined as HBsAg positive confirmed by HBV DNA
Original Primary Outcome Measures  ICMJE
 (submitted: December 7, 2012)
Infant's Hepatitis B infection status, defined as HBsAg positive confirmed by HBV DNA [ Time Frame: 6 months of age ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 11, 2018)
  • 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.
  • 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
  • Infant's HBV infection status [ 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
  • Weight, height and head circumference for age [ Time Frame: at 6 months and 12 months of age ]
    Weight, length/height and head circumference WHO Z scores
Original Secondary Outcome Measures  ICMJE
 (submitted: December 7, 2012)
  • Occurrence of maternal and infant adverse events (AE), including ICH Maternal and Infants Serious Adverse Events and DAIDS grade 3/4 signs and symptoms, regardless of their relatedness to the study treatment. [ Time Frame: from enrollment to 12 months postpartum ]
  • Occurrence of acute exacerbation of hepatitis B after study treatment interruption [ Time Frame: Following planned discontinuation of study treatment up to 12 months postpartum ]
    The acute exacerbation or flare of hepatitis B is defined as ALT more than 10 times Upper Limit of Normal (ULN) and more than twice the baseline value
  • Infant's HBV infection status, defined as HBsAg positive confirmed by HBV DNA, [ Time Frame: at or after 6 months through 12 months of age ]
  • Infant growth related outcomes, including weight, height and HC Z-scores [ Time Frame: at 6 months and 12 months of age ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Maternal Antiviral Prophylaxis to Prevent Perinatal Transmission of Hepatitis B Virus in Thailand
Official Title  ICMJE 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.
Brief Summary

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.

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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE
  • Hepatitis B Chronic Infection
  • Pregnancy
Intervention  ICMJE
  • Drug: tenofovir disoproxil fumarate
    administration: tablet 300 mg, once a day, from enrollment at 28 weeks' gestation until 2 months postpartum
    Other Names:
    • Viread
    • TDF
    • tenofovir
  • Drug: placebo
    administration: one tablet, once a day, from enrollment at 28 weeks' gestation until 2 months postpartum
Study Arms  ICMJE
  • Experimental: Tenofovir disoproxil fumarate
    tenofovir disoproxil fumarate, 300 mg tablets
    Intervention: Drug: tenofovir disoproxil fumarate
  • Placebo Comparator: Placebo
    matching placebo (of tenofovir disoproxil fumarate)
    Intervention: Drug: placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Estimated Enrollment  ICMJE
 (submitted: December 7, 2012)
328
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE October 2018
Actual Primary Completion Date December 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Thailand
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01745822
Other Study ID Numbers  ICMJE U01HD071889( U.S. NIH Grant/Contract )
U01HD071889 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Plan Description: Pending completion of analysis planned in the protocol
Responsible Party GONZAGUE JOURDAIN, Institut de Recherche pour le Developpement
Study Sponsor  ICMJE Institut de Recherche pour le Developpement
Collaborators  ICMJE
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
  • Centers for Disease Control and Prevention
  • Gilead Sciences
Investigators  ICMJE
Principal Investigator: Gonzague Jourdain, MD, PhD Institut de Recherche pour le Developpement
PRS Account Institut de Recherche pour le Developpement
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP