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

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ClinicalTrials.gov Identifier: NCT03476083
Recruitment Status : Recruiting
First Posted : March 23, 2018
Last Update Posted : December 12, 2019
Sponsor:
Information provided by (Responsible Party):
New Discovery LLC

Study Description
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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.

Condition or disease Intervention/treatment Phase
Hepatitis B Infection Congenital Malformation Birth Defect Viremia Chronic Infection Drug: Tenofovir Disoproxil Fumarate (TDF) 300 mg oral daily. Phase 4

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 280 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
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
Actual Study Start Date : June 10, 2018
Estimated Primary Completion Date : May 2021
Estimated Study Completion Date : May 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Group A
This is the experimental group. Participating mothers will receive Tenofovir Disoproxil Fumarate (TDF) 300 mg oral 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 and additional hepatitis B (HBV) vaccine at the age of week 4 and week 24. HBIg will be omitted for the infants in this group.
 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.
Other Names:
  • HBIg 200 IU im for infants in the group B
  • HBV vaccine 10 ug im for all infants
Active Comparator: Group B
This is the comparative group. Participating mothers will receive Tenofovir Disoproxil Fumarate (TDF) 300 mg oral 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 and additional hepatitis B vaccine at the age of week 4 and week 24.
 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.
Other Names:
  • HBIg 200 IU im for infants in the group B
  • HBV vaccine 10 ug im for all infants


Outcome Measures
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Primary Outcome Measures :
  1. Assessment on the proportion of infants who are infected with hepatitis B at the age of 28 weeks in the two groups [ Time Frame: From the date of birth to age of 28 weeks. ]
    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.


Secondary Outcome Measures :
  1. Assessment on congenital defects and/or malformation rates in each infant group for comparison [ Time Frame: From the date of birth to age of 28 weeks. ]
    Congenital defects and/or malformation rates are defined as the proportion of infants with the aforementioned abnormalities discovered during the study period.

  2. Assessment on the reduction of maternal HBV DNA levels at delivery [ Time Frame: From the date of randomization until delivery. ]
    Assess the reduction of maternal HBV DNA levels at delivery when compared to the baseline before initiating TDF.

  3. Maternal serological outcomes during the study: Percentage of mothers who loss/seroconversion of HBsAg or/and HBeAg during the study [ Time Frame: From the date of randomization until postpartum week 28. ]
    Assess the percentage of mothers who loss/seroconversion of HBsAg or/and HBeAg during the study.

  4. Adverse events of both mothers and infants [ Time Frame: From the date of screening until postpartum week 28. ]
    Assess the percentage of mothers or infants who have adverse events during the study.

  5. Tolerability of TDF therapy: Percentage of mothers who discontinue on TDF therapy due to the adverse event(s) during the study [ Time Frame: From the date of randomization until delivery. ]
    Assess the percentage of mothers who discontinue on TDF therapy due to the adverse event(s) during the study.


Eligibility Criteria
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Ages Eligible for Study:   20 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03476083


Contacts
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Contact: Xiuli Chen, MD +86-13363887189 13363887189@163.com
Contact: Erhei Dai, MD +86-13323119296 daieh2008@126.com

Locations
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China, Beijing
Beijing Youan Hospital, Capital Medical University Recruiting
Beijing, Beijing, China, 100069
Contact: Hua Zhang, MD    +86-13717850635    13717850635@163.com   
Contact: Huaibin Zou, MD    +86-13720084736    zhbin03@126.com   
Principal Investigator: Hua Zhang, MD         
Sub-Investigator: Zhongping Duan, MD         
China, Chongqing
Southwest Hospital Recruiting
Chongqing, Chongqing, China, 400038
Contact: Jie Wang, MD    +86-15826122759    876468834@qq.com   
Contact: Shilian Li, MD    +86-15223423922    cqmu032@163.com   
Principal Investigator: Yuming Wang, MD         
Sub-Investigator: Yangsu Tu, MD         
China, Guangdong
Guangzhou Women and Children's Medical Center, Guangzhou Medical University Recruiting
Guangzhou, Guangdong, China, 510623
Contact: Jinjuan Wu, MD    +86-13632446716    14867150@qq.com   
Contact: Thomas Q Zheng, MD    +86-18902268420    zhengqintian@yahoo.com   
Principal Investigator: Thomas Q Zheng, MD         
Sub-Investigator: Ping He, MD         
China, Hebei
The Fifth Hospital of Shijiazhuang Recruiting
Shijiazhuang, Hebei, China, 050021
Contact: Hongxia Tian, MD    +86-17332925370    2631238023@qq.com   
Contact: Suwen Li, MD    +86-13363876968    lisuwen158311@163.com   
Principal Investigator: Erhei Dai, MD         
Sub-Investigator: Suwen Li, MD         
Shijiazhuang Maternal and Child Health Care Hospital Recruiting
Shijiazhuang, Hebei, China, 050051
Contact: Cuili Yang, MD    +86-18731160875    yangcuili0821@163.com   
Contact: Jing Liu, MD    +86-15032791700    liujingteti@163.com   
Principal Investigator: Zhongfu Mo, MD         
Sub-Investigator: Cuili Yang, MD         
China, Shaanxi
Department of Infectious Diseases, the First Affiliated Hospital of Xi'an Jiaotong University Recruiting
Xi'an, Shaanxi, China, 710061
Contact: Taotao Yan, MD    +86-18691485175    437550036@qq.com   
Contact: Yingren Zhao, MD    +86-13509187086    zhaoyingren@mail.xjtu.edu.cn   
Sub-Investigator: Tianyan Chen, MD         
Principal Investigator: Yingren Zhao, MD         
China, Shenzhen
The Third People's Hospital of Shenzhen Recruiting
Shenzhen, Shenzhen, China, 518112
Contact: Liuqing Yang, MD    +86-13352983979    350281813@qq.com   
Contact: Yanjie Li, MD    +86-15096103342    1129404985@qq.com   
Principal Investigator: Yingxia Liu, MD         
Sub-Investigator: Liuqing Yang, MD         
Sponsors and Collaborators
New Discovery LLC
Investigators
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Study Chair: Calvin Q Pan, MD Leading Principle Investigator, NYU Langone Health, NYU School of Medicine, NY
Study Director: Erhei Dai, MD The Fifth Hospital of Shijiazhuang, Shijiazhuang, Hebei Province, China
More Information
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Publications:
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.

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Responsible Party: New Discovery LLC
ClinicalTrials.gov Identifier: NCT03476083    
Other Study ID Numbers: US-G10-P616
(2018) 462 No: HGRSL20180412 ( Other Identifier: Ministry of Science and Technology of China, HGRM Office )
First Posted: March 23, 2018    Key Record Dates
Last Update Posted: December 12, 2019
Last Verified: December 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by New Discovery LLC:
Mother to Child Transmission
Hepatitis B Infection
Congenital Defects or Malformation
Hepatitis B Vaccine
 Hepatitis B Immunoglobulin
Pregnancy
Antiviral Treatment
Additional relevant MeSH terms:
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Infection
Communicable Diseases
Hepatitis A
Hepatitis B
Viremia
Hepatitis
Congenital Abnormalities
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepadnaviridae Infections
 DNA Virus Infections
Sepsis
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Tenofovir
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents