Clinical trial NCT04211805: Maternal Therapy With TAF Versus TDF to Prevent Vertical Transmission of Hepatitis B
Official title: Real World Study of Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate to Prevent Vertical Transmission of Hepatitis B in Mothers With High Viral Load
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Hepatitis B, Chronic
Pregnancy Related
Keywords: Chronic Hepatitis B
Pregnancy
Mother to Child Transmission
Vertical Transmission
Lead sponsor: New Discovery LLC
Sponsor class: INDUSTRY
First posted: 2019-12-26
Enrollment: 450
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: 225 consecutive chronically infected hepatitis B mothers who are willing to receive tenofovir alafenamide (TAF) treatment and another consecutive 225 who are willing to receive tenofovir disoproxil fumarate (TDF) treatment at eleven centers across China for high viremic load during pregnancy will be enrolled and followed prospectively for data collection. These patients underwent TAF/TDF treatment in their respective care centers and will be grouped together in Group A for TAF treatment and Group B for TDF treatment for primary and secondary analysis.

Brief summary: Immunoprophylaxis failure of hepatitis B (HBV) remains a concern and has been reported in approximately 10-30% of infants born to highly viremic mothers with HBeAg-positive. Maternal HBV DNA \>6log10 copies/mL (or 200,000 IU/mL) is the major independent risk for mother-to-child transmission (MTCT). Two recent random controlled trial (RCT) studies have shown that the use of Tenofovir Disoproxil Fumarate (TDF) in highly viremic HBsAg positive mothers may safely reduce the rate of MTCT when compared between groups of TDF treated and untreated patients. Tenofovir Alafenamide (TAF) is the successor to TDF, and both drugs have a similar mechanism of action to reduce HBV DNA levels and normalize serum alanine aminotransferase (ALT) in chronic hepatitis B patients (CHB) with few adverse effects. TAF however, has a better safety profile with less adverse effects to bone mineral density and renal function. The present prospective, double-arm study is to evaluate the non-inferiority in the efficacy and safety of TAF therapy versus TDF therapy in highly viremic mothers and their infants for the prevention of MTCT in the real world setting.

Detailed description: This is a prospective, double-arm, multi-center study conducted through 11 centers across China. Consecutive 450 mothers who are eligible for the study will be enrolled during gestational weeks 24-28 to receive TDF or TAF based on the patients' preference, and the treatment will be discontinued right after the delivery. All infants will receive HBV vaccination plus HBIg within 12 hours after birth and the additional HBV vaccination at the age of 4 weeks and 24 weeks. Primary outcome assessment will be performed at the infants' age of 28 will be collected to evaluate non-inferiority in the safety and efficacy of TAF therapy versus TDF therapy. These parameters will be extracted from test results of serum biochemistries, hematology, and virology, including but not limited to aspartate aminotransferase (AST), ALT, HBV DNA levels, and serological status of HBV (HBsAg, HBeAb, HBcAb, HBeAg, and HBsAg).

All aforementioned clinical parameters will be extracted from mothers at the following timepoints for assessment: the baseline, i.e. the start of TAF/TDF treatment, gestational weeks 28, 32, 36, on delivery, and at postpartum weeks 24-28. For the infant, information from two timepoints, at birth and at infant age of 28 weeks, will be collected. This information regarding the infant will include the physical parameters weight, height, head circumference, HBV DNA levels, HBV serological status, if they received hepatitis B immunoglobin (HBIg), if they received the complete series of HBV vaccine. All relevant information regarding the patient will be logged into a password-protected computer for primary and secondary analysis.

Group A: 225 participating mothers will receive TAF (oral 25 mg tablet daily) starting at gestational week 24-28 of pregnancy and continue until delivery. The mothers will be followed together with their infants until postpartum week 28.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. Group B: 225 participating mothers will receive TDF (oral 300 mg tablet daily) starting at gestational week 24-28 of pregnancy and continue until delivery. Patients in group B will have similar follow-up schedules as those in the Group A. 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:

1. Pregnant female, above 18 years of age and under 40 years of age.
2. Gestational age between 12-14 weeks (The screening on patients can be started at gestational week 12).
3. Documented compensated and stable chronic hepatitis B defined by all of the following:

   * HBsAg persistently positive \> 6 months.
   * Clinical history, physical findings, and test results are compatible with compensated chronic hepatitis B.
4. Detectable maternal serum HBsAg and HBeAg at the screening visit.
5. Maternal serum HBV DNA levels exceeding 200,000 IU/mL by the COBAS Amplicor HBV PCR assay at screening visits.
6. Patient is willing and able to comply with the study drug regimen and all other study requirements. Patient is also willing to prevent another pregnancy in 28 weeks after delivery of the current baby.
7. Patient and her husband (both father and mother of the child) understand the risk and are willing to have the mother participating in the study. The mother must be willing and able to provide written informed consent to participate in the study.

Exclusion Criteria:

Patients will be excluded if they have any one of the following:

1. Creatinine clearance \<100 mL/min (using the Cockcroft-Gault method based on serum creatinine and ideal body weight) or hypo-phosphoremia (below normal range).
2. History of renal events on adefovir or history of resistance to adefovir.
3. Hemoglobin \<8 g/dL, or neutrophil count \<1000/uL, or ALT \>5 times ULN, or total bilirubin \>2 mg/dL; or albumin \<25gm/L, or abnormal creatinine level, or abnormal BUN levels.
4. History of abortion, or congenital malformation, or child infected with HBV in a prior pregnancy.
5. Biological father of the child (current pregnancy) has CHB.
6. Significant renal, cardiovascular, pulmonary, or neurological disease that may impact the subject's participation in the study as per the opinion of the investigator.

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 the age of 24-28 weeks
measure: Assessment on Congenital Defects and/or Malformation Rates in Each Infant Group for Comparison
timeFrame: from the date of birth to Infant's age of 24-28 weeks
Secondary outcomes:
measure: Assessment on the change in Maternal HBV DNA Levels at Delivery
timeFrame: from gestational week 24-28 week to delivery
measure: Maternal Serological Outcomes During the Study: Percentage of Mothers who Loss/Seroconversion of HBsAg or/and HBeAg During the Study
timeFrame: from gestational week 24-28 week to postpartum week 28
measure: Incidence of Treatment-Emergent Adverse Events in Mothers as Stratified by the CTCAE v 5.0
timeFrame: Gestational week 24-28 until Postpartum Week 28
measure: Incidence of Treatment-Emergent Adverse Events in Infants as Stratified by the CTCAE v 5.0
timeFrame: Delivery until Infant age Week 28
measure: Percentage of Mothers with Alanine transferase (ALT) Levels Within the Normal Limit
timeFrame: Gestational week 24-28 until Postpartum week 28
measure: Percentage of Mothers with Aspartamine transferase (AST) Levels Within the Normal Limit
timeFrame: Gestational week 24-28 until Postpartum week 28
measure: Group A: Proportion of Infants Born to Mothers Who Received TAF, Whose Physical Growth Characteristics Stay Within the Published National Normal Range.
timeFrame: Delivery to Infant age 28 weeks
measure: Group B: Proportion of Infants Born to Mothers Who Received TDF, Whose Physical Growth Characteristics Stay Within the Published National Normal Range.
timeFrame: Delivery to Infant age 28 weeks
measure: Tolerability of TDF vs TAF Therapy: Percentage of Mothers who Discontinue Therapy Due to the Adverse Event(s) During the Study.
timeFrame: Gestational week 24-28 until Delivery
Other outcomes:
Locations:
city: Shapingba
country: China
facility: Pingdingshan Hospital of Chongqing Public Health Medical Treatment Center
state: Chongqing
city: Fuzhou
country: China
facility: First Affiliated Hospital of Fujian Medical University
state: Fujian
city: Shenzhen
country: China
facility: The Seventh Affiliated Hospital, Sun Yat-sen University
state: Guangdong
city: Haikou
country: China
facility: Hainan General Hospital
state: Hainan
city: Qinhuangdao
country: China
facility: The Third Hospital of Qinhuangdao
state: Hebei
city: Harbin
country: China
facility: The Fourth Hospital of Harbin Medical University
state: Heilonjiang
city: Changsha
country: China
facility: Xiangya Hospital, Central South University
state: Hunan
city: Ganzhou
country: China
facility: Ganzhou Fifth People's Hospital
state: Jiangxi
city: Shenyang
country: China
facility: Shengjing Hospital of China Medical University
state: Liaoning
city: Jinshan
country: China
facility: Shanghai Public Health Clinical Center, Fudan University
state: Shanghai
city: Yuyao
country: China
facility: Yuyao People's Hospital of Zhejiang Province
state: Zhejiang
Study officials:
affiliation: Beijing Ditan Hospital, Capital Medical University; NYU Langone Health, NY, USA
name: Calvin Pan, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Zou H, Chen Y, Duan Z, Zhang H. Protective effect of hepatitis B vaccine combined with two-dose hepatitis B immunoglobulin on infants born to HBsAg-positive mothers. PLoS One. 2011;6(10):e26748. doi: 10.1371/journal.pone.0026748. Epub 2011 Oct 28.
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: 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: Wiseman E, Fraser MA, Holden S, Glass A, Kidson BL, Heron LG, Maley MW, Ayres A, Locarnini SA, Levy MT. Perinatal transmission of hepatitis B virus: an Australian experience. Med J Aust. 2009 May 4;190(9):489-92. doi: 10.5694/j.1326-5377.2009.tb02524.x.