<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02995005</url>
  </required_header>
  <id_info>
    <org_study_id>JHSPH-TDF</org_study_id>
    <nct_id>NCT02995005</nct_id>
    <nct_alias>NCT03167229</nct_alias>
  </id_info>
  <brief_title>Tenofovir in Early Pregnancy to Prevent Mother-to-child Transmission of Hepatitis B Virus</brief_title>
  <official_title>Prevention of Mother-to-child Transmission of Hepatitis B Virus: a One Arm, Open Label Intervention Study to Estimate the Optimal Timing of Tenofovir (TDF) in Pregnancy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Johns Hopkins Bloomberg School of Public Health</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Thrasher Research Fund</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Shoklo Malaria Research Unit</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Chiang Mai University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Oxford</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Johns Hopkins Bloomberg School of Public Health</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Mother-to-child transmission (MTCT) of hepatitis B virus (HBV) remains the major mode of&#xD;
      transmission in most high and intermediate HBV endemic areas, despite existing WHO&#xD;
      immunoprophylaxis recommendations. This immunoprophylaxis regimen, if given optimally, can&#xD;
      prevent 75-80% of HBV MTCT, but optimal implementation is difficult because it requires&#xD;
      administering monovalent HBV vaccine and hepatitis B immunoglobulin (HBIg) within 24 hours of&#xD;
      birth. Due to the barriers of giving HBIg, the World Health Organization (WHO) states,&#xD;
      &quot;…owing to concerns related to supply, safety and cost, the use of HBIg is not feasible in&#xD;
      most settings.&quot; Clearly, global control of HBV transmission will require improved MTCT&#xD;
      prevention. Therefore, the investigators hypothesize that treating HBV early in pregnancy&#xD;
      will lead to undetectable HBV DNA levels at delivery and prevention of MTCT of HBV without&#xD;
      HBIg; a concept that has already been proven with HIV. Tenofovir disoproxil fumarate (TDF),&#xD;
      an approved anti-HBV drug, is promising to prevent MTCT of HBV due to its high potency&#xD;
      against hepatitis B and its safety record in pregnant women. A randomized, controlled&#xD;
      clinical trial (RCT) will be necessary to determine if TDF given to HBV-infected pregnant&#xD;
      women early in pregnancy plus vaccine to the newborn can decrease MTCT of HBV without HBIg.&#xD;
      However, before embarking on a RCT, several critical knowledge gaps need to be addressed&#xD;
      including the ideal timing for TDF initiation. The purpose of this proposal is to address&#xD;
      these knowledge gaps.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The investigators hypothesize that anti-HBV therapy given in the late first or early second&#xD;
      trimester achieves undetectable HBV DNA at delivery in &gt;=95% of pregnant women with chronic&#xD;
      hepatitis B. The one-arm, open-label, interventional study aims: 1, To estimate the time to&#xD;
      complete HBV DNA suppression (&lt;100 IU/ml) in 170 HBV DNA positive women who start TDF in the&#xD;
      late first or early second trimester; and to estimate the proportion of women with HBV DNA&#xD;
      &lt;100 IU/ml at delivery. 2, To address potential barriers to and the efficacy of implementing&#xD;
      TDF in early pregnancy to prevent mother-to-child transmission of hepatitis B. The&#xD;
      investigators will measure potential barriers to acceptability and effectiveness of this&#xD;
      intervention: adherence, potential hepatitis B flares in mothers (safety), and the proportion&#xD;
      of hepatitis B infections in the offspring at 1 year of age (efficacy).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 24, 2018</start_date>
  <completion_date type="Actual">January 31, 2023</completion_date>
  <primary_completion_date type="Actual">January 31, 2023</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Single group study.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>No masking, just one interventional group.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>The time (from inclusion through delivery; up to 6 months) to HBV DNA suppression (&lt;100 IU/ml)</measure>
    <time_frame>Up to 9 months</time_frame>
    <description>HBV DNA will be monitored every month</description>
  </primary_outcome>
  <primary_outcome>
    <measure>The proportion of women with undetectable HBV DNA at delivery</measure>
    <time_frame>At delivery</time_frame>
    <description>HBV DNA will be monitored at delivery.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Proportion of hepatitis B flares in mothers postpartum</measure>
    <time_frame>Monthly measured for 3 months after stopping TDF.</time_frame>
    <description>All women will continue on study for 3 months after stopping TDF to measure their alanine aminotransferase (ALT) and aspartate aminotransferase (AST) monthly to detect a flare, which will be defined as &gt;5x baseline or &gt;10x the upper limit of normal. If at the end of the 3 months, there has been no change in ALT and AST, then the mothers will be discharged from the study. If there is an increase in liver enzymes but not a true flare, they will be followed for an additional 3 months with monthly ALT testing.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The proportion of women who adhered to TDF treatment during the course of the study (from inclusion through 1 month after delivery; up to 7 months; drug levels)</measure>
    <time_frame>Up to 9 months</time_frame>
    <description>Measurement of tenofovir drug levels</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The proportion of women who adhered to TDF treatment during the course of the study (from inclusion through 1 month after delivery; up to 7 months; drug accountability)</measure>
    <time_frame>Up to 9 months</time_frame>
    <description>Drug accountability using standard methods (subtracting the number of tablets left from the number of tablets distributed).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The proportion of women who adhered to TDF treatment during the course of the study (from inclusion through 1 month after delivery; up to 7 months; questionnaire)</measure>
    <time_frame>Up to 9 months</time_frame>
    <description>All women will be surveyed at monthly visits and at birth to measure adherence including actionable barriers.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The proportion of hepatitis B infections in the offspring at 1 year of age</measure>
    <time_frame>Between month 2 and 12 month</time_frame>
    <description>Testing for HBsAg in children between 2 and 12 months of age.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">98</enrollment>
  <condition>Hepatitis B</condition>
  <arm_group>
    <arm_group_label>Tenofovir Disoproxil Fumarate</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Women early in pregnancy (end of first or beginning second trimester) will be treated with TDF to determine the efficacy of this strategy to bring &gt;=95% of women to undetectable HBV DNA levels at delivery.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tenofovir Disoproxil Fumarate</intervention_name>
    <description>300 mg daily</description>
    <arm_group_label>Tenofovir Disoproxil Fumarate</arm_group_label>
    <other_name>Viread</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Pregnant women aged 18 and over&#xD;
&#xD;
          -  HBsAg positive&#xD;
&#xD;
          -  In the 12th-20th week of pregnancy&#xD;
&#xD;
          -  Willing to take TDF daily during pregnancy&#xD;
&#xD;
          -  Providing written informed consent&#xD;
&#xD;
          -  Plans to deliver at Shoklo Malaria Research Unit (SMRU)&#xD;
&#xD;
          -  Able and willing to comply with study requirements&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Anti-HIV positive&#xD;
&#xD;
          -  Negative qualitative HBV DNA if HBeAg negative&#xD;
&#xD;
          -  On immunosuppressive therapy&#xD;
&#xD;
          -  Elevated creatinine&#xD;
&#xD;
          -  History of kidney disease&#xD;
&#xD;
          -  Short cervix&#xD;
&#xD;
          -  History of pregnancy complications or prior pre-term labor&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>49 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Stephan Ehrhardt, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Johns Hopkins Bloomberg School of Public Health</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Shoklo Malaria Research Unit</name>
      <address>
        <city>Mae Sot</city>
        <country>Thailand</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Thailand</country>
  </location_countries>
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  <reference>
    <citation>Hendrix CW, Chen BA, Guddera V, Hoesley C, Justman J, Nakabiito C, Salata R, Soto-Torres L, Patterson K, Minnis AM, Gandham S, Gomez K, Richardson BA, Bumpus NN. MTN-001: randomized pharmacokinetic cross-over study comparing tenofovir vaginal gel and oral tablets in vaginal tissue and other compartments. PLoS One. 2013;8(1):e55013. doi: 10.1371/journal.pone.0055013. Epub 2013 Jan 30.</citation>
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  </reference>
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  </reference>
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    <citation>Seserko LA, Emory JF, Hendrix CW, Marzinke MA. The development and validation of an UHPLC-MS/MS method for the rapid quantification of the antiretroviral agent dapivirine in human plasma. Bioanalysis. 2013 Nov;5(22):2771-83. doi: 10.4155/bio.13.256.</citation>
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  </reference>
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    <citation>Minnis AM, Gandham S, Richardson BA, Guddera V, Chen BA, Salata R, Nakabiito C, Hoesley C, Justman J, Soto-Torres L, Patterson K, Gomez K, Hendrix CW. Adherence and acceptability in MTN 001: a randomized cross-over trial of daily oral and topical tenofovir for HIV prevention in women. AIDS Behav. 2013 Feb;17(2):737-47. doi: 10.1007/s10461-012-0333-8.</citation>
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  <verification_date>October 2022</verification_date>
  <study_first_submitted>December 8, 2016</study_first_submitted>
  <study_first_submitted_qc>December 13, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 16, 2016</study_first_posted>
  <last_update_submitted>February 3, 2023</last_update_submitted>
  <last_update_submitted_qc>February 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>mother to child transmission</keyword>
  <keyword>hepatitis B</keyword>
  <keyword>tenofovir</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatitis A</mesh_term>
    <mesh_term>Hepatitis B</mesh_term>
    <mesh_term>Hepatitis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tenofovir</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>The investigators are currently developing an individual participant data (IPD) sharing plan.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_time_frame>Data will become available 6 months after publication of the main report.</ipd_time_frame>
    <ipd_access_criteria>Permission by corresponding author</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02995005
org study id: JHSPH-TDF
nct id: NCT02995005
nct alias: NCT03167229
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
Mother-to-child transmission (MTCT) of hepatitis B virus (HBV) remains the major mode of
      transmission in most high and intermediate HBV endemic areas, despite existing WHO
      immunoprophylaxis recommendations. This immunoprophylaxis regimen, if given optimally, can
      prevent 75-80% of HBV MTCT, but optimal implementation is difficult because it requires
      administering monovalent HBV vaccine and hepatitis B immunoglobulin (HBIg) within 24 hours of
      birth. Due to the barriers of giving HBIg, the World Health Organization (WHO) states,
      "…owing to concerns related to supply, safety and cost, the use of HBIg is not feasible in
      most settings." Clearly, global control of HBV transmission will require improved MTCT
      prevention. Therefore, the investigators hypothesize that treating HBV early in pregnancy
      will lead to undetectable HBV DNA levels at delivery and prevention of MTCT of HBV without
      HBIg; a concept that has already been proven with HIV. Tenofovir disoproxil fumarate (TDF),
      an approved anti-HBV drug, is promising to prevent MTCT of HBV due to its high potency
      against hepatitis B and its safety record in pregnant women. A randomized, controlled
      clinical trial (RCT) will be necessary to determine if TDF given to HBV-infected pregnant
      women early in pregnancy plus vaccine to the newborn can decrease MTCT of HBV without HBIg.
      However, before embarking on a RCT, several critical knowledge gaps need to be addressed
      including the ideal timing for TDF initiation. The purpose of this proposal is to address
      these knowledge gaps.
The investigators hypothesize that anti-HBV therapy given in the late first or early second
      trimester achieves undetectable HBV DNA at delivery in >=95% of pregnant women with chronic
      hepatitis B. The one-arm, open-label, interventional study aims: 1, To estimate the time to
      complete HBV DNA suppression (<100 IU/ml) in 170 HBV DNA positive women who start TDF in the
      late first or early second trimester; and to estimate the proportion of women with HBV DNA
      <100 IU/ml at delivery. 2, To address potential barriers to and the efficacy of implementing
      TDF in early pregnancy to prevent mother-to-child transmission of hepatitis B. The
      investigators will measure potential barriers to acceptability and effectiveness of this
      intervention: adherence, potential hepatitis B flares in mothers (safety), and the proportion
      of hepatitis B infections in the offspring at 1 year of age (efficacy).
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Single group study.
primary purpose: Prevention
masking: None (Open Label)
masking description: No masking, just one interventional group.
measure: The time (from inclusion through delivery; up to 6 months) to HBV DNA suppression (<100 IU/ml)
time frame: Up to 9 months
description: HBV DNA will be monitored every month
measure: The proportion of women with undetectable HBV DNA at delivery
time frame: At delivery
description: HBV DNA will be monitored at delivery.
measure: Proportion of hepatitis B flares in mothers postpartum
time frame: Monthly measured for 3 months after stopping TDF.
description: All women will continue on study for 3 months after stopping TDF to measure their alanine aminotransferase (ALT) and aspartate aminotransferase (AST) monthly to detect a flare, which will be defined as >5x baseline or >10x the upper limit of normal. If at the end of the 3 months, there has been no change in ALT and AST, then the mothers will be discharged from the study. If there is an increase in liver enzymes but not a true flare, they will be followed for an additional 3 months with monthly ALT testing.
measure: The proportion of women who adhered to TDF treatment during the course of the study (from inclusion through 1 month after delivery; up to 7 months; drug levels)
time frame: Up to 9 months
description: Measurement of tenofovir drug levels
measure: The proportion of women who adhered to TDF treatment during the course of the study (from inclusion through 1 month after delivery; up to 7 months; drug accountability)
time frame: Up to 9 months
description: Drug accountability using standard methods (subtracting the number of tablets left from the number of tablets distributed).
measure: The proportion of women who adhered to TDF treatment during the course of the study (from inclusion through 1 month after delivery; up to 7 months; questionnaire)
time frame: Up to 9 months
description: All women will be surveyed at monthly visits and at birth to measure adherence including actionable barriers.
measure: The proportion of hepatitis B infections in the offspring at 1 year of age
time frame: Between month 2 and 12 month
description: Testing for HBsAg in children between 2 and 12 months of age.
arm group label: Tenofovir Disoproxil Fumarate
arm group type: Experimental
description: Women early in pregnancy (end of first or beginning second trimester) will be treated with TDF to determine the efficacy of this strategy to bring >=95% of women to undetectable HBV DNA levels at delivery.
intervention type: Drug
intervention name: Tenofovir Disoproxil Fumarate
description: 300 mg daily
arm group label: Tenofovir Disoproxil Fumarate
other name: Viread
criteria: 
gender: Female
minimum age: 16 Years
maximum age: 49 Years
healthy volunteers: No
last name: Stephan Ehrhardt, MD
role: Principal Investigator
affiliation: Johns Hopkins Bloomberg School of Public Health
facility: 
country: Thailand
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responsible party type: Sponsor
mesh term: Hepatitis A
mesh term: Hepatitis B
mesh term: Hepatitis
mesh term: Tenofovir
sharing ipd: Yes
ipd description: The investigators are currently developing an individual participant data (IPD) sharing plan.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd time frame: Data will become available 6 months after publication of the main report.
ipd access criteria: Permission by corresponding author