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

Primary Purpose

Hepatitis B Infection, Congenital Malformation, Birth Defect

Status

Recruiting

Phase

Phase 4

Locations

China

Study Type

Interventional

Intervention

Tenofovir Disoproxil Fumarate (TDF) 300 mg oral daily.

About this trial

This is an interventional prevention trial for Hepatitis B Infection focused on measuring Mother to Child Transmission, Hepatitis B Infection, Congenital Defects or Malformation, Hepatitis B Vaccine, Hepatitis B Immunoglobulin, Pregnancy, Antiviral Treatment

Eligibility Criteria

20 Years - 35 Years (Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

Beijing Youan Hospital, Capital Medical UniversityRecruiting
Southwest HospitalRecruiting
Guangzhou Women and Children's Medical Center, Guangzhou Medical UniversityRecruiting
The Fifth Hospital of ShijiazhuangRecruiting
Shijiazhuang Maternal and Child Health Care HospitalRecruiting
Department of Infectious Diseases, the First Affiliated Hospital of Xi'an Jiaotong UniversityRecruiting
The Third People's Hospital of ShenzhenRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Group A

Group B

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

Adverse events of both mothers and infants

Assess the percentage of mothers or infants who have adverse events during the study.

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.

Full Information

NCT ID

NCT03476083

First Posted

March 18, 2018

Last Updated

December 11, 2019

Sponsor

New Discovery LLC

1. Study Identification

Unique Protocol Identification Number

NCT03476083

Brief Title

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

2. Study Status

Record Verification Date

December 2019

Overall Recruitment Status

Recruiting

Study Start Date

June 10, 2018 (Actual)

Primary Completion Date

May 2021 (Anticipated)

Study Completion Date

May 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

New Discovery LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

280 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Group A

Arm Type

Experimental

Arm Description

Arm Title

Group B

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Tenofovir Disoproxil Fumarate (TDF) 300 mg oral daily.

Other Intervention Name(s)

HBIg 200 IU im for infants in the group B, HBV vaccine 10 ug im for all infants

Intervention Description

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.

Primary Outcome Measure Information:

Title

Assessment on the proportion of infants who are infected with hepatitis B at the age of 28 weeks in the two groups

Description

Time Frame

From the date of birth to age of 28 weeks.

Secondary Outcome Measure Information:

Title

Assessment on congenital defects and/or malformation rates in each infant group for comparison

Description

Congenital defects and/or malformation rates are defined as the proportion of infants with the aforementioned abnormalities discovered during the study period.

Time Frame

From the date of birth to age of 28 weeks.

Title

Assessment on the reduction of maternal HBV DNA levels at delivery

Description

Assess the reduction of maternal HBV DNA levels at delivery when compared to the baseline before initiating TDF.

Time Frame

From the date of randomization until delivery.

Title

Maternal serological outcomes during the study: Percentage of mothers who loss/seroconversion of HBsAg or/and HBeAg during the study

Description

Assess the 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.

Title

Adverse events of both mothers and infants

Description

Assess the percentage of mothers or infants who have adverse events during the study.

Time Frame

From the date of screening until postpartum week 28.

Title

Tolerability of TDF therapy: Percentage of mothers who discontinue on TDF therapy due to the adverse event(s) during the study

Description

Assess the 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.

10. Eligibility

Sex

Female

Gender Based

Yes

Minimum Age & Unit of Time

20 Years

Maximum Age & Unit of Time

35 Years

Accepts Healthy Volunteers

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Xiuli Chen, MD

Phone

+86-13363887189

13363887189@163.com

First Name & Middle Initial & Last Name or Official Title & Degree

Erhei Dai, MD

Phone

+86-13323119296

daieh2008@126.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Calvin Q Pan, MD

Organizational Affiliation

Leading Principle Investigator, NYU Langone Health, NYU School of Medicine, NY

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Erhei Dai, MD

Organizational Affiliation

The Fifth Hospital of Shijiazhuang, Shijiazhuang, Hebei Province, China

Official's Role

Study Director

Facility Information:

Facility Name

Beijing Youan Hospital, Capital Medical University

City

Beijing

State/Province

Beijing

ZIP/Postal Code

100069

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Hua Zhang, MD

Phone

+86-13717850635

13717850635@163.com

First Name & Middle Initial & Last Name & Degree

Huaibin Zou, MD

Phone

+86-13720084736

zhbin03@126.com

First Name & Middle Initial & Last Name & Degree

Hua Zhang, MD

First Name & Middle Initial & Last Name & Degree

Zhongping Duan, MD

Facility Name

Southwest Hospital

City

Chongqing

State/Province

Chongqing

ZIP/Postal Code

400038

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jie Wang, MD

Phone

+86-15826122759

876468834@qq.com

First Name & Middle Initial & Last Name & Degree

Shilian Li, MD

Phone

+86-15223423922

cqmu032@163.com

First Name & Middle Initial & Last Name & Degree

Yuming Wang, MD

First Name & Middle Initial & Last Name & Degree

Yangsu Tu, MD

Facility Name

Guangzhou Women and Children's Medical Center, Guangzhou Medical University

City

Guangzhou

State/Province

Guangdong

ZIP/Postal Code

510623

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jinjuan Wu, MD

Phone

+86-13632446716

14867150@qq.com

First Name & Middle Initial & Last Name & Degree

Thomas Q Zheng, MD

Phone

+86-18902268420

zhengqintian@yahoo.com

First Name & Middle Initial & Last Name & Degree

Thomas Q Zheng, MD

First Name & Middle Initial & Last Name & Degree

Ping He, MD

Facility Name

The Fifth Hospital of Shijiazhuang

City

Shijiazhuang

State/Province

Hebei

ZIP/Postal Code

050021

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Hongxia Tian, MD

Phone

+86-17332925370

2631238023@qq.com

First Name & Middle Initial & Last Name & Degree

Suwen Li, MD

Phone

+86-13363876968

lisuwen158311@163.com

First Name & Middle Initial & Last Name & Degree

Erhei Dai, MD

First Name & Middle Initial & Last Name & Degree

Suwen Li, MD

Facility Name

Shijiazhuang Maternal and Child Health Care Hospital

City

Shijiazhuang

State/Province

Hebei

ZIP/Postal Code

050051

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Cuili Yang, MD

Phone

+86-18731160875

yangcuili0821@163.com

First Name & Middle Initial & Last Name & Degree

Jing Liu, MD

Phone

+86-15032791700

liujingteti@163.com

First Name & Middle Initial & Last Name & Degree

Zhongfu Mo, MD

First Name & Middle Initial & Last Name & Degree

Cuili Yang, MD

Facility Name

Department of Infectious Diseases, the First Affiliated Hospital of Xi'an Jiaotong University

City

Xi'an

State/Province

Shaanxi

ZIP/Postal Code

710061

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Taotao Yan, MD

Phone

+86-18691485175

437550036@qq.com

First Name & Middle Initial & Last Name & Degree

Yingren Zhao, MD

Phone

+86-13509187086

zhaoyingren@mail.xjtu.edu.cn

First Name & Middle Initial & Last Name & Degree

Tianyan Chen, MD

First Name & Middle Initial & Last Name & Degree

Yingren Zhao, MD

Facility Name

The Third People's Hospital of Shenzhen

City

Shenzhen

State/Province

Shenzhen

ZIP/Postal Code

518112

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Liuqing Yang, MD

Phone

+86-13352983979

350281813@qq.com

First Name & Middle Initial & Last Name & Degree

Yanjie Li, MD

Phone

+86-15096103342

1129404985@qq.com

First Name & Middle Initial & Last Name & Degree

Yingxia Liu, MD

First Name & Middle Initial & Last Name & Degree

Liuqing Yang, MD

12. IPD Sharing Statement

Citations:

PubMed Identifier

22682147

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.

Results Reference

background

PubMed Identifier

22079509

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.

Results Reference

background

PubMed Identifier

24168259

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.

Results Reference

background

PubMed Identifier

26778725

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.

Results Reference

background

PubMed Identifier

25362571

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.

Results Reference

background

PubMed Identifier

27305192

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.

Results Reference

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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.

Results Reference

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

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