Tenofovir Disoproxil Fumarate in Combination of Hepatitis B Vaccine for Preventing Hepatitis B Vertical Transmission

Hepatitis B Infection Clinical Trial

Official title:

Tenofovir Disoproxil Fumarate in Combination of Hepatitis B Vaccine With the Omission of Immune Globulin to Prevent Hepatitis B Transmission in Mother With High Viral Load: A Multi-Center, Prospective, Randomized and Open-Label Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03476083
• Other study ID #: US-G10-P616
• Secondary ID: (2018) 462 No: H
• Status: Recruiting
• Phase: Phase 4
• Start date: June 10, 2018
• Est. completion date: May 2024

Study information

• Verified date: December 2019
• Source: New Discovery LLC
• Contact: Xiuli Chen, MD
• Phone: +86-13363887189
• Email: 13363887189[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Immunoprophylaxis with two hepatitis B vaccinations following the hepatitis B immune globulin (HBIg) and hepatitis B vaccine at birth is largely effective in protecting infants from hepatitis B virus (HBV) infection. However, hepatitis B infection due to immunoprophylaxis failure often occurs in approximately 10% of infants who are born to highly viremic mothers with HBeAg-positive. Maternal HBV DNA > 200,000 IU/mL is the major independent risk for mother-to-child transmission (MTCT). A recent randomized controlled trial has shown that Tenofovir Disoproxil Fumarate (TDF) use during the third trimester of pregnancy could safely reduce the rate of MTCT with few adverse effects when combined with the administration of the standard immunoprophylaxis to the infants. However, HBIg is expensive and not available in many developing countries, resulting approximately 30% of infant infection when they received only HBV vaccination. The present study aims to investigate if highly viremic mothers who are treated with TDF from the second trimester to delivery in combination of infant's standard series of HBV vaccinations (omission of HBIg) have a comparable MTCT rates, when compared to those of mothers who receive TDF at the third trimester in combination of infant's standard HBV vaccinations and a birth dose of HBIg.

Description:

This is a multicenter, prospective, randomized, open-label and parallel two arm study starting from week 14-16 of pregnancy to post-partum week 28. The enrollment from approximately 7 centers will be in blocks for sample balance. By using the randomized table, 280 HBeAg-positive pregnant women with chronic hepatitis B (CHB) will be randomized in a 1:1 ratio in to two arms. Group assignments will be also stratified by the maternal HBV DNA levels >9 log10 versus ≤ 9 log10 IU/mL.

Group A: This is the experimental group. Participating mothers will receive TDF (oral 300 mg tablet daily) starting at gestational weeks 14-16 and continue until delivery. The mothers will be followed together with their infants until postpartum week 28. Infants will receive hepatitis B vaccine at birth (within 12 hours) and additional hepatitis B vaccine at the age of week 4 and week 24. HBIg will be omitted for the infants in this group. However, the birth dose of HBIg will be provided to infants born to mothers who have poor control of maternal viremia (i.e. the levels of HBV DNA >200,000 IU/mL before delivery). Group B: This is the comparative group. Participating mothers will receive TDF (oral 300 mg tablet daily) starting at gestational weeks 28 and continue until delivery. Patients in group B will have similar follow-up schedules as those in the experimental group. Infants will receive hepatitis B vaccine plus HBIg at birth (within 12 hours) and additional hepatitis B vaccine at the age of week 4 and week 24.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 280
• Est. completion date: May 2024
• Est. primary completion date: May 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 20 Years to 35 Years

Eligibility

Inclusion Criteria:

• HBeAg-positive CHB mothers

• Age of 20-35 years old

• Serum HBV DNA levels > 200,000 IU/mL

• Gestational age between 12-14 weeks.

• Both mother and father of the child have the ability to understand and are willing to consent to the study.

Exclusion Criteria:

• Co-infection with (HIV)-1, or hepatitis A, C, D, E or sexual transmitted diseases (STD)

• History of abortion or congenital malformation in a prior pregnancy

• Treatment experience (except when antivirals were used for MTCT prevention in a previous pregnancy and discontinued >6 months prior to the current pregnancy)

• History of renal dysfunction; evidence of liver cancer or decompensation

• Estimated creatinine clearance (CLCr) <100 mL/min (using the Cockcroft-Gault method based on serum creatinine and ideal body weight)

• Hypo-phosphoremia; hemoglobin <8 g/dL; neutrophil count <1,000//µL; alanine aminotransferase >5 times upper limit of the normal; total bilirubin >2 mg/dL; albumin <25gm/L;

• Clinical signs of threatened miscarriage

• Ultrasonographic evidence of fetal deformity

• Concurrent treatment with nephrotoxic drugs, steroids, cytotoxic drugs, nonsteroidal anti-inflammatory drugs, or immune modulators;

• Recipient of solid organ or bone marrow transplant

• Significant renal, cardiovascular, pulmonary, neurological disease or other health conditions in the opinion of the investigator

• Fetus's biological father had CHB infection

Related Conditions & MeSH terms

• Birth Defect
• Chronic Infection
• Communicable Diseases
• Congenital Abnormalities
• Congenital Malformation
• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B Infection
• Infection
• Viremia

Intervention

Drug:
• Tenofovir Disoproxil Fumarate (TDF) 300 mg oral daily.
All mothers will receive TDF therapy. However, group A will initiate TDF at the gestational week of 14-16, while group B will initiate TDF at the gestational week of 28. All infants will receive a series of three hepatitis B vaccines (at birth, age of weeks 4 and 24). In addition, the infants in the group B will receive HBIg injection at birth.

Locations

Country	Name	City	State
China	Beijing Youan Hospital, Capital Medical University	Beijing	Beijing
China	Southwest Hospital	Chongqing	Chongqing
China	Guangzhou Women and Children's Medical Center, Guangzhou Medical University	Guangzhou	Guangdong
China	The Third People's Hospital of Shenzhen	Shenzhen	Shenzhen
China	Shijiazhuang Maternal and Child Health Care Hospital	Shijiazhuang	Hebei
China	The Fifth Hospital of Shijiazhuang	Shijiazhuang	Hebei
China	Department of Infectious Diseases, the First Affiliated Hospital of Xi'an Jiaotong University	Xi'an	Shaanxi

Sponsors (1)

Lead Sponsor	Collaborator
New Discovery LLC

Country where clinical trial is conducted

China, 

References & Publications (7)

Lee LY, Aw MM, Saw S, Rauff M, Tong PY, Lee GH. Limited benefit of hepatitis B immunoglobulin prophylaxis in children of hepatitis B e antigen-negative mothers. Singapore Med J. 2016 Oct;57(10):566-569. doi: 10.11622/smedj.2015194. Epub 2015 Dec 29. — View Citation

Machaira M, Papaevangelou V, Vouloumanou EK, Tansarli GS, Falagas ME. Hepatitis B vaccine alone or with hepatitis B immunoglobulin in neonates of HBsAg+/HBeAg- mothers: a systematic review and meta-analysis. J Antimicrob Chemother. 2015 Feb;70(2):396-404. doi: 10.1093/jac/dku404. Epub 2014 Oct 31. Review. — View Citation

Ott JJ, Stevens GA, Wiersma ST. The risk of perinatal hepatitis B virus transmission: hepatitis B e antigen (HBeAg) prevalence estimates for all world regions. BMC Infect Dis. 2012 Jun 9;12:131. doi: 10.1186/1471-2334-12-131. — View Citation

Pan CQ, Duan Z, Dai E, Zhang S, Han G, Wang Y, Zhang H, Zou H, Zhu B, Zhao W, Jiang H; China Study Group for the Mother-to-Child Transmission of Hepatitis B. Tenofovir to Prevent Hepatitis B Transmission in Mothers with High Viral Load. N Engl J Med. 2016 Jun 16;374(24):2324-34. doi: 10.1056/NEJMoa1508660. — View Citation

Pan CQ, Duan ZP, Bhamidimarri KR, Zou HB, Liang XF, Li J, Tong MJ. An algorithm for risk assessment and intervention of mother to child transmission of hepatitis B virus. Clin Gastroenterol Hepatol. 2012 May;10(5):452-9. doi: 10.1016/j.cgh.2011.10.041. Epub 2011 Nov 9. Review. — View Citation

Pan, C. Q.; Chang, T. T.; Bae, S. H.; Brunetto, M.; Coffin, C.; Lau, A.; Mo, S.; Flaherty, J. F.; Gaggar, A.; Subramanian, G. M.; Nguyen, M. H.; Gurel, S.; Thompson, A.; Gane, E. J. Viral kinetics in women of child bearing potential with chronic hepatitis B virus following treatment with tenofovir alafenamide or tenofovir disoproxil fumarate. J Hepatol. 2017;66 S258-S259.

Pande C, Sarin SK, Patra S, Kumar A, Mishra S, Srivastava S, Bhutia K, Gupta E, Mukhopadhyay CK, Dutta AK, Trivedi SS. Hepatitis B vaccination with or without hepatitis B immunoglobulin at birth to babies born of HBsAg-positive mothers prevents overt HBV transmission but may not prevent occult HBV infection in babies: a randomized controlled trial. J Viral Hepat. 2013 Nov;20(11):801-10. doi: 10.1111/jvh.12102. Epub 2013 Apr 23. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Assessment on the proportion of infants who are infected with hepatitis B at the age of 28 weeks in the two groups	Compare MTCT rates between the two study groups and demonstrate non-inferiority in efficacy. MTCT rate is defined as the proportion of infants with serum HBV DNA >20 IU/mL and/or HBsAg positivity at 28 weeks of age.	From the date of birth to age of 28 weeks.
Secondary	Assessment on congenital defects and/or malformation rates in each infant group for comparison	Congenital defects and/or malformation rates are defined as the proportion of infants with the aforementioned abnormalities discovered during the study period.	From the date of birth to age of 28 weeks.
Secondary	Assessment on the reduction of maternal HBV DNA levels at delivery	Assess the reduction of maternal HBV DNA levels at delivery when compared to the baseline before initiating TDF.	From the date of randomization until delivery.
Secondary	Maternal serological outcomes during the study: Percentage of mothers who loss/seroconversion of HBsAg or/and HBeAg during the study	Assess the percentage of mothers who loss/seroconversion of HBsAg or/and HBeAg during the study.	From the date of randomization until postpartum week 28.
Secondary	Adverse events of both mothers and infants	Assess the percentage of mothers or infants who have adverse events during the study.	From the date of screening until postpartum week 28.
Secondary	Tolerability of TDF therapy: Percentage of mothers who discontinue on TDF therapy due to the adverse event(s) during the study	Assess the percentage of mothers who discontinue on TDF therapy due to the adverse event(s) during the study.	From the date of randomization until delivery.