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

Study Overview
=================
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.

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.

Conditions
-----------------
Pregnancy, Hepatitis B Chronic Infection

Intervention / Treatment
-----------------
* Drug: tenofovir disoproxil fumarate
* Drug: placebo


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tenofovir disoproxil fumarate<br>tenofovir disoproxil fumarate, 300 mg tablets | Drug: tenofovir disoproxil fumarate<br>* administration: tablet 300 mg, once a day, from enrollment at 28 weeks' gestation until 2 months postpartum<br>* Other names: tenofovir;|
| Placebo Comparator: Placebo<br>matching placebo (of tenofovir disoproxil fumarate) | Drug: placebo<br>* administration: one tablet, once a day, from enrollment at 28 weeks' gestation until 2 months postpartum<br>|

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 | 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 | 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 | 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 | 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 | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hepatitis B, Hepatitis B sAg, Hepatitis B eAg, pregnancy