Clinical trial NCT03476083: Tenofovir Disoproxil Fumarate in Combination of Hepatitis B Vaccine for Preventing Hepatitis B Vertical Transmission
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Hepatitis B Infection
Congenital Malformation
Birth Defect
Viremia
Chronic Infection
Keywords: Mother to Child Transmission
Hepatitis B Infection
Congenital Defects or Malformation
Hepatitis B Vaccine
Hepatitis B Immunoglobulin
Pregnancy
Antiviral Treatment
Lead sponsor: New Discovery LLC
Sponsor class: INDUSTRY
First posted: 2018-03-23
Enrollment: 280
Sex: FEMALE
Minimum age (years): 20
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Assessment on the proportion of infants who are infected with hepatitis B at the age of 28 weeks in the two groups
timeFrame: From the date of birth to age of 28 weeks.
Secondary outcomes:
measure: Assessment on congenital defects and/or malformation rates in each infant group for comparison
timeFrame: From the date of birth to age of 28 weeks.
measure: Assessment on the reduction of maternal HBV DNA levels at delivery
timeFrame: From the date of randomization until delivery.
measure: Maternal serological outcomes during the study: Percentage of mothers who loss/seroconversion of HBsAg or/and HBeAg during the study
timeFrame: From the date of randomization until postpartum week 28.
measure: Adverse events of both mothers and infants
timeFrame: From the date of screening until postpartum week 28.
measure: Tolerability of TDF therapy: Percentage of mothers who discontinue on TDF therapy due to the adverse event(s) during the study
timeFrame: From the date of randomization until delivery.
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Youan Hospital, Capital Medical University
state: Beijing
city: Chongqing
country: China
facility: Southwest Hospital
state: Chongqing
city: Guangzhou
country: China
facility: Guangzhou Women and Children's Medical Center, Guangzhou Medical University
state: Guangdong
city: Shijiazhuang
country: China
facility: The Fifth Hospital of Shijiazhuang
state: Hebei
city: Shijiazhuang
country: China
facility: Shijiazhuang Maternal and Child Health Care Hospital
state: Hebei
city: Xi'an
country: China
facility: Department of Infectious Diseases, the First Affiliated Hospital of Xi'an Jiaotong University
state: Shaanxi
city: Shenzhen
country: China
facility: The Third People's Hospital of Shenzhen
state: Shenzhen
Study officials:
affiliation: Leading Principle Investigator, NYU Langone Health, NYU School of Medicine, NY
name: Calvin Q Pan, MD
role: STUDY_CHAIR
affiliation: The Fifth Hospital of Shijiazhuang, Shijiazhuang, Hebei Province, China
name: Erhei Dai, MD
role: STUDY_DIRECTOR
References:
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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.
citation: 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.
citation: 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.
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.
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.
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.