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

• ClinicalTrials.gov Identifier: NCT01745822
• Recruitment Status: Completed
• First Posted: December 10, 2012
• Results First Posted: March 5, 2021
• Last Update Posted: March 5, 2021
• Sponsor: Institut de Recherche pour le Developpement
• 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: December 6, 2012
• First Posted Date: December 10, 2012
• Results First Submitted Date: April 28, 2020
• Results First Posted Date: March 5, 2021
• Last Update Posted Date: March 5, 2021
• Study Start Date: January 2013
• Actual Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 12, 2021)

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

• Original Primary Outcome Measures (submitted: December 7, 2012): Infant's Hepatitis B infection status, defined as HBsAg positive confirmed by HBV DNA [ Time Frame: 6 months of age ]

Current Secondary Outcome Measures (submitted: February 12, 2021)

• 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.
• 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
• 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
• 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.

Original Secondary Outcome Measures (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: Maternal Antiviral Prophylaxis to Prevent Perinatal Transmission of Hepatitis B Virus in Thailand
• Official Title: 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: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention

Condition

• Hepatitis B Chronic Infection
• Pregnancy

Intervention

• 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

• 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 *

• Jourdain G, Ngo-Giang-Huong N, Cressey TR, Hua L, Harrison L, Tierney C, Salvadori N, Decker L, Traisathit P, Sirirungsi W, Khamduang W, Bowonwatanuwong C, Puthanakit T, Siberry GK, Watts DH, Murphy TV, Achalapong J, Hongsiriwon S, Klinbuayaem V, Thongsawat S, Chung RT, Pol S, Chotivanich N. Prevention of mother-to-child transmission of hepatitis B virus: a phase III, placebo-controlled, double-blind, randomized clinical trial to assess the efficacy and safety of a short course of tenofovir disoproxil fumarate in women with hepatitis B virus e-antigen. BMC Infect Dis. 2016 Aug 9;16:393. doi: 10.1186/s12879-016-1734-5.
• Jourdain G, Ngo-Giang-Huong N, Harrison L, Decker L, Tierney C, Cressey TR, Achalapong J, Siberry GK, Nelson NP, and Chotivanich N. TDF to prevent perinatal hepatitis B virus transmission: a randomized trial (iTAP). Conference on Retroviruses and Opportunistic Infections (CROI) Abstract 584LB; 2017 February 13; Seattle, WA, USA. http://www.croiconference.org/sessions/tdf-prevent-perinatal-hepatitis-b-virus-transmission-randomized-trial-itap
• Jourdain G, Ngo-Giang-Huong N, Harrison L, Decker L, Khamduang W, Tierney C, Salvadori N, Cressey TR, Sirirungsi W, Achalapong J, Yuthavisuthi P, Kanjanavikai P, Na Ayudhaya OP, Siriwachirachai T, Prommas S, Sabsanong P, Limtrakul A, Varadisai S, Putiyanun C, Suriyachai P, Liampongsabuddhi P, Sangsawang S, Matanasarawut W, Buranabanjasatean S, Puernngooluerm P, Bowonwatanuwong C, Puthanakit T, Klinbuayaem V, Thongsawat S, Thanprasertsuk S, Siberry GK, Watts DH, Chakhtoura N, Murphy TV, Nelson NP, Chung RT, Pol S, Chotivanich N. Tenofovir versus Placebo to Prevent Perinatal Transmission of Hepatitis B. N Engl J Med. 2018 Mar 8;378(10):911-923. doi: 10.1056/NEJMoa1708131.
• Jourdain G, Harrison LJ, Ngo-Giang-Huong N, Cressey TR, Decker L, Tierney C, Achalapong J, Kanjanavikai P, Luvira A, Srirompotong U, Murphy TV, Nelson N, Siberry GK, Pol S, for the iTAP Study Group. iTAP trial: maternal and infant efficacy and safety results 12 months after delivery. CROI, 4-7 March 2018, Boston, USA. #1316, Oral Presentation O-11
• Salvadori N, Fan B, Teeyasoontranon W, Ngo-Giang-Huong N, Phanomcheong S, Luvira A, Puangsombat A, Suwannarat A, Srirompotong U, Putiyanun C, Kourtis A, Bulterys M, Siberry GK, Jourdain G. TDF prophylaxis for PMTCT of HBV: effect on maternal and infant bone mineral density. CROI, 4-7 March 2018, Boston, USA. #1174. Poster and Themed Discussion TD-09
• Cressey TR, Harrison L, Achalapong J, Kanjanavikai P, Patamasingh Na Ayudhaya O, Liampongsabuddhi P, Siriwachirachai T, Putiyanun C, Suriyachai P, Tierney C, Salvadori N, Chinwong D, Decker L, Tawon Y, Murphy TV, Ngo-Giang-Huong N, Siberry GK, Jourdain G; iTAP Study Team. Tenofovir Exposure during Pregnancy and Postpartum in Women Receiving Tenofovir Disoproxil Fumarate for the Prevention of Mother-to-Child Transmission of Hepatitis B Virus. Antimicrob Agents Chemother. 2018 Nov 26;62(12):e01686-18. doi: 10.1128/AAC.01686-18. Print 2018 Dec.
• Salvadori N, Fan B, Teeyasoontranon W, Ngo-Giang-Huong N, Phanomcheong S, Luvira A, Puangsombat A, Suwannarat A, Srirompotong U, Putiyanun C, Cressey TR, Decker L, Khamduang W, Harrison L, Tierney C, Shepherd JA, Kourtis AP, Bulterys M, Siberry GK, Jourdain G. Maternal and Infant Bone Mineral Density 1 Year After Delivery in a Randomized, Controlled Trial of Maternal Tenofovir Disoproxil Fumarate to Prevent Mother-to-child Transmission of Hepatitis B Virus. Clin Infect Dis. 2019 Jun 18;69(1):144-146. doi: 10.1093/cid/ciy982.
• Ngo-Giang-Huong N, Salvadori N, Khamduang W, Cressey TR, Harrison LJ, Decker L, Tierney C, Jullapong A, Murphy TV, Nelson N, Siberry GK, Chung RT, Pol S, Jourdain G. Hepatitis B virus DNA level changes in HBeAg+ pregnant women receiving TDF for PMTCT. Conference on Retroviruses and Opportunistic Infections (CROI), Seattle, WA, 4-7 Mar 2019
• Bukkems V, Smolders E, Jourdain G, Hawkins D, Achalapong J, Kanjanavikai P, Taylor G, Prommas S, Burger D, Colbers A, Cressey TR, for the iTAP Study Team & PANNA network. Tenofovir plasma concentrations in pregnant women: comparison of hepatitis B and HIV-infected patients. 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis & Other Antiviral Drugs. Noordwijk, the Netherlands, 14-16-May 2019
• Jourdain G, Traisathit P, Salvadori N, Wangsaeng N, Khamduang W, Ngo-Giang-Huong N, for the iTAP Study Group. Immunization response in infants born to HBsAg+ and HBeAg+ mothers receiving TDF (ID 3681). Conference on Retroviruses and Opportunistic Infections (CROI), Hynes Convention Center, USA, 8-11 Mar 2020, Virtual Conference

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 12, 2021): 654
• Original Estimated Enrollment (submitted: December 7, 2012): 328
• Actual Study Completion Date: October 2018
• Actual Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Thailand

Administrative Information

• NCT Number: NCT01745822
• Other Study ID Numbers: 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

• Plan to Share IPD: Undecided
• Plan Description: Pending completion of analysis planned in the protocol

• Current Responsible Party: GONZAGUE JOURDAIN, Institut de Recherche pour le Developpement
• Original Responsible Party: Gonzague Jourdain, Institut de Recherche pour le Developpement, Chargé de recherches
• Current Study Sponsor: Institut de Recherche pour le Developpement
• Original Study Sponsor: Same as current

Collaborators

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

Investigators

• Principal Investigator: Gonzague Jourdain, MD, PhD; Institut de Recherche pour le Developpement

• PRS Account: Institut de Recherche pour le Developpement
• Verification Date: February 2021