Clinical trial NCT01745822: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hepatitis B Chronic Infection
Pregnancy
Keywords: Hepatitis B
Hepatitis B sAg
Hepatitis B eAg
pregnancy
Lead sponsor: Institut de Recherche pour le Developpement
Sponsor class: OTHER_GOV
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Centers for Disease Control and Prevention
name: Gilead Sciences
First posted: 2012-12-10
Enrollment: 654
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Percentage of Infants With Hepatitis B Infection at 6 Months of Age
timeFrame: 6 months of age
Secondary outcomes:
measure: Percentage of Participants With Adverse Events
timeFrame: from enrollment (28 weeks' gestation) to 12 months postpartum
measure: Percentage of Participants With Flares After Study Treatment Interruption
timeFrame: Following planned discontinuation of study treatment up to 12 months postpartum
measure: Percentage of Infants With Hepatitis B Infection at or After 6 Months Through 12 Months of Age
timeFrame: at or after 6 months through 12 months of age
measure: Weight, Height and Head Circumference for Age
timeFrame: assessed at 6 months and 12 months of age, 6 months reported
Other outcomes:
Locations:
city: Mae Chan
country: Thailand
facility: Mae Chan Hospital
state: Chiangrai
city: Bang Lamung
country: Thailand
facility: Banglamung Hospital
state: Chon Buri
city: Nakhon Ratchasima
country: Thailand
facility: Maharat Nakhon Ratchasima Hospital
state: Nakhon Ratchasrima
city: Chiang Kham
country: Thailand
facility: Chiang Kham Hospital
state: Phayao
city: Bangkok
country: Thailand
facility: Bhumibol Adulyadej Hospital
city: Bangkok
country: Thailand
facility: Nopparat Rajathanee Hospital
city: Chanthaburi
country: Thailand
facility: Prapokklao Hospital
city: Chiang Mai
country: Thailand
facility: Health Promotion Center Region 10
city: Chiang Mai
country: Thailand
facility: Nakornping Hospital
city: Chiang Rai
country: Thailand
facility: Chiangrai Prachanukroh Hospital
city: Chon Buri
country: Thailand
facility: Chonburi Regional Hospital
city: Khon Kaen
country: Thailand
facility: Khon Kaen Hospital
city: Lampang
country: Thailand
facility: Lampang Hospital
city: Lamphun
country: Thailand
facility: Lamphun Hospital
city: Phayao
country: Thailand
facility: Phayao Provincial Hospital
city: Samut Prakan
country: Thailand
facility: Samutprakarn Hospital
city: Samut Sakhon
country: Thailand
facility: Samutsakhon Hospital
Study officials:
affiliation: Institut de Recherche pour le Developpement
name: Gonzague Jourdain, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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
citation: 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.
citation: 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
citation: 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
citation: 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.
citation: 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.
citation: 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
citation: 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
citation: 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