<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/NCT04496882</url>
  </required_header>
  <id_info>
    <org_study_id>201911095MIPD</org_study_id>
    <nct_id>NCT04496882</nct_id>
  </id_info>
  <brief_title>Chronic Hepatitis b Patients Switch to tAf After Discontinuation of Nucleoside Analogue</brief_title>
  <acronym>CHANGE</acronym>
  <official_title>The Clinical Efficacy of Tenofovir Alafenamide-switching Therapy in Patients With Chronic Hepatitis B Experiencing Clinical Flare-up After Discontinuation of Nucleos[t]Ide Analogues Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Taiwan University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Taiwan University Hospital, Yun-Lin Branch</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Taipei City Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Chiayi Christian Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Dalin Tzu Chi General Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>E-DA Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>National Taiwan University Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      We will conduct a phase 4, multicenter, open-label trial at 7 academic centers in Taiwan.&#xD;
&#xD;
      Chronic hepatitis B patients receiving oral antiviral therapy (entecavir [ETV], tenofovir&#xD;
      disoproxil fumarate [TDF]) for at least 2 years, and fulfil the following nucleos(t)ide&#xD;
      analogs discontinuation criteria. After nucleos(t)ide analogs discontinuation, patients had a&#xD;
      clinical relapse and retreatment regimen switches to TAF.&#xD;
&#xD;
      The protocol will be approved by Institutional Review Board (IRB) or Research ethic committee&#xD;
      (REC) of each site and will be conducted in accordance with the principles of Declaration of&#xD;
      Helsinki and the International Conference on Harmonization for Good Clinical Practice. Each&#xD;
      patient provides written informed consent before enrollment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Tenofovir alafenamide (TAF) is a new generation of oral antiviral drugs with similar&#xD;
      antiviral activities to tenofovir disoproxil fumarate (TDF) and reduces the adverse effects&#xD;
      of nephrotoxicity and bone mineral density reduction. This drug has already been reimbursed&#xD;
      by National Health Insurance, and can be used for the treatment of patients with chronic&#xD;
      hepatitis B.&#xD;
&#xD;
      This is a single-arm prospective clinical trial to enroll patients who discontinued entecavir&#xD;
      (ETV) and tenofovir disoproxil fumarate (TDF) and experienced a clinical hepatitis flare up.&#xD;
      They can be retreated with TAF for 48 weeks without postponing a 3-month observation period&#xD;
      for alanine aminotransferase (ALT) level. The virological control, ALT level recovery, and&#xD;
      changes in liver fibrosis, hepatitis B surface antigen, hepatitis B core-associated antigen,&#xD;
      and renal function will be observed during retreatment. In addition, a group of patients with&#xD;
      the same characteristics who received retreatment with entecavir or TDF will be collected as&#xD;
      a control group for comparison. We believe this study can help us understand the clinical&#xD;
      benefits of switching to TAF for retreatment after hepatitis flare in patients to discontinue&#xD;
      oral antiviral agents.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">September 9, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2022</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Rate of virological remission (HBV DNA &lt;20 IU/mL)</measure>
    <time_frame>48 weeks</time_frame>
    <description>We will calculate the rate of virological remission (HBV DNA &lt;20 IU/mL) after retreatment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Rate of ALT normalization (ALT &lt; 40 U/L) after retreatment</measure>
    <time_frame>48 weeks</time_frame>
    <description>We will calculate the rate of ALT normalization (ALT &lt; 40 U/L) after retreatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of HBsAg change after retreatment compared with baseline</measure>
    <time_frame>48 weeks</time_frame>
    <description>We will investigate the rate of HBsAg change after retreatment compared with the baseline HBsAg</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of HBcrAg change after retreatment compared with baseline</measure>
    <time_frame>48 weeks</time_frame>
    <description>We will investigate the rate of hepatitis B core-related antigen (HBcrAg) change after retreatment compared with baseline HBcrAg</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of M2BPGi level change after retreatment compared with baseline</measure>
    <time_frame>48 weeks</time_frame>
    <description>We will investigate the rate of Mac-2 binding protein glycosylation isomer (M2BPGi) level change after retreatment compared with baseline M2BPGi level</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">260</enrollment>
  <condition>Chronic Hepatitis b</condition>
  <condition>Hepatitis B Reactivation</condition>
  <arm_group>
    <arm_group_label>Switching therapy cohort</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>single arm, open label Patients will receive Vemlidy (tenofovir alafenamide, TAF) 25mg, daily for 48 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Historical continuing therapy cohort</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>By retrospectively review medical records, The patients continued the original regimen (ETV, TDF) for retreatment (within 3 months of clinical relapse)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vemlidy</intervention_name>
    <description>25mg Tenofovir Alafenamide</description>
    <arm_group_label>Switching therapy cohort</arm_group_label>
    <other_name>Tenofovir Alafenamide (TAF)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria A. Switching therapy cohort&#xD;
&#xD;
          1. Chronic hepatitis B patients receiving oral antiviral therapy (ETV, TDF) for at least&#xD;
             2 years, and fulfil the following NUCs discontinuation criteria (1)HBeAg-positive&#xD;
             patients achieving HBeAg seroclearance, and received at least 1-year consolidation&#xD;
             therapy (2) HBeAg-negative patients achieving undetectable HBV DNA for more than 1&#xD;
             year (on 3 occasions, 6 months apart)&#xD;
&#xD;
          2. After NUC discontinuation, patients had a clinical relapse (HBV DNA &gt; 2000 IU/mL, and&#xD;
             ALT &gt; 2x ULN)&#xD;
&#xD;
          3. The retreatment regimen switches to TAF (within 3 months of clinical relapse)&#xD;
&#xD;
        B. Historical continuing therapy cohort&#xD;
&#xD;
          1. Chronic hepatitis B patients receiving oral antiviral therapy (ETV, TDF) for at least&#xD;
             2 years, and fulfil the following NUCs discontinuation criteria (1) HBeAg-positive&#xD;
             patients achieving HBeAg seroclearance, and received at least 1-year consolidation&#xD;
             therapy (2) HBeAg-negative patients achieving undetectable HBV DNA for more than 1&#xD;
             year(on 3 occasions, 6 months apart)&#xD;
&#xD;
          2. After NUC discontinuation, patients had a clinical relapse (HBV DNA &gt; 2000 IU/mL, and&#xD;
             ALT &gt; 2x ULN)&#xD;
&#xD;
          3. The patients continued the original regimen (ETV, TDF) for retreatment (within 3&#xD;
             months of clinical relapse)&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          1. Patients who do not fulfill the discontinuation criteria&#xD;
&#xD;
          2. Patients who have HCV, HDV or HIV co-infection&#xD;
&#xD;
          3. Patients who discontinue lamivudine, adefovir, or telbivudine therapy&#xD;
&#xD;
          4. Patients with liver cirrhosis by ultrasonography and clinical diagnosis&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Tung-Hung Su, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Taiwan University Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Tung-Hung Su, MD, PhD</last_name>
    <phone>886972651694</phone>
    <email>tunghungsu@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Pei-Ying Yang, MS</last_name>
    <phone>886965277228</phone>
    <email>pying0208@gmail.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Buddhist Tzu Chi General Hospital, Da-Lin Branch</name>
      <address>
        <city>Chiayi City</city>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kuo-Chih Tseng, MD</last_name>
      <phone>88652648000</phone>
      <phone_ext>3240</phone_ext>
      <email>tsengkuochih@gmail.com</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Chia-Yi Christian Hospital</name>
      <address>
        <city>Chiayi City</city>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Chi-Yi Chen, MD</last_name>
      <phone>88652765041</phone>
      <phone_ext>5264</phone_ext>
      <email>5137ccy@gmail.com</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>National Taiwan University Hospital, Yun-Lin branch</name>
      <address>
        <city>Douliu</city>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Yu-Jen Fang, MD</last_name>
      <phone>886972655715</phone>
      <email>toby851072@gmail.com</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>E-da hospital</name>
      <address>
        <city>Kaohsiung</city>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Yao-Chun Hsu, MD, PhD</last_name>
      <phone>886975209520</phone>
      <email>holdenhsu@gmail.com</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>National Taiwan University Hospital</name>
      <address>
        <city>Taipei</city>
        <zip>100</zip>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Tung-Hung Su, MD, PhD</last_name>
      <phone>886972651694</phone>
      <email>tunghungsu@gmail.com</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Buddhist Tzu-Chi General Hospital Taipei Branch</name>
      <address>
        <city>Taipei</city>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Chia-Chi Wang, MD</last_name>
      <phone>886266289779</phone>
      <phone_ext>2317</phone_ext>
      <email>uld888@yahoo.com.tw</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Taipei City Hospital, Renai Branch</name>
      <address>
        <city>Taipei</city>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Chih-Lin Lin, MD</last_name>
      <phone>886227099558</phone>
      <email>lcl@tpech.gov.tw</email>
    </contact>
  </location>
  <location_countries>
    <country>Taiwan</country>
  </location_countries>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>July 26, 2020</study_first_submitted>
  <study_first_submitted_qc>July 30, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 3, 2020</study_first_posted>
  <last_update_submitted>August 4, 2021</last_update_submitted>
  <last_update_submitted_qc>August 4, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 5, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>HBV,clinical relapse,Vemlidy (TAF)</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 B, Chronic</mesh_term>
    <mesh_term>Hepatitis</mesh_term>
    <mesh_term>Hepatitis, Chronic</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>No</sharing_ipd>
  </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/NCT04496882
org study id: 201911095MIPD
nct id: NCT04496882
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
We will conduct a phase 4, multicenter, open-label trial at 7 academic centers in Taiwan.

      Chronic hepatitis B patients receiving oral antiviral therapy (entecavir [ETV], tenofovir
      disoproxil fumarate [TDF]) for at least 2 years, and fulfil the following nucleos(t)ide
      analogs discontinuation criteria. After nucleos(t)ide analogs discontinuation, patients had a
      clinical relapse and retreatment regimen switches to TAF.

      The protocol will be approved by Institutional Review Board (IRB) or Research ethic committee
      (REC) of each site and will be conducted in accordance with the principles of Declaration of
      Helsinki and the International Conference on Harmonization for Good Clinical Practice. Each
      patient provides written informed consent before enrollment.
Tenofovir alafenamide (TAF) is a new generation of oral antiviral drugs with similar
      antiviral activities to tenofovir disoproxil fumarate (TDF) and reduces the adverse effects
      of nephrotoxicity and bone mineral density reduction. This drug has already been reimbursed
      by National Health Insurance, and can be used for the treatment of patients with chronic
      hepatitis B.

      This is a single-arm prospective clinical trial to enroll patients who discontinued entecavir
      (ETV) and tenofovir disoproxil fumarate (TDF) and experienced a clinical hepatitis flare up.
      They can be retreated with TAF for 48 weeks without postponing a 3-month observation period
      for alanine aminotransferase (ALT) level. The virological control, ALT level recovery, and
      changes in liver fibrosis, hepatitis B surface antigen, hepatitis B core-associated antigen,
      and renal function will be observed during retreatment. In addition, a group of patients with
      the same characteristics who received retreatment with entecavir or TDF will be collected as
      a control group for comparison. We believe this study can help us understand the clinical
      benefits of switching to TAF for retreatment after hepatitis flare in patients to discontinue
      oral antiviral agents.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Rate of virological remission (HBV DNA <20 IU/mL)
time frame: 48 weeks
description: We will calculate the rate of virological remission (HBV DNA <20 IU/mL) after retreatment
measure: Rate of ALT normalization (ALT < 40 U/L) after retreatment
time frame: 48 weeks
description: We will calculate the rate of ALT normalization (ALT < 40 U/L) after retreatment
measure: Rate of HBsAg change after retreatment compared with baseline
time frame: 48 weeks
description: We will investigate the rate of HBsAg change after retreatment compared with the baseline HBsAg
measure: Rate of HBcrAg change after retreatment compared with baseline
time frame: 48 weeks
description: We will investigate the rate of hepatitis B core-related antigen (HBcrAg) change after retreatment compared with baseline HBcrAg
measure: Rate of M2BPGi level change after retreatment compared with baseline
time frame: 48 weeks
description: We will investigate the rate of Mac-2 binding protein glycosylation isomer (M2BPGi) level change after retreatment compared with baseline M2BPGi level
arm group label: Switching therapy cohort
arm group type: Experimental
description: single arm, open label Patients will receive Vemlidy (tenofovir alafenamide, TAF) 25mg, daily for 48 weeks
arm group label: Historical continuing therapy cohort
arm group type: No Intervention
description: By retrospectively review medical records, The patients continued the original regimen (ETV, TDF) for retreatment (within 3 months of clinical relapse)
intervention type: Drug
intervention name: Vemlidy
description: 25mg Tenofovir Alafenamide
arm group label: Switching therapy cohort
other name: Tenofovir Alafenamide (TAF)
criteria: 
gender: All
minimum age: 20 Years
maximum age: 99 Years
healthy volunteers: No
last name: Tung-Hung Su, MD, PhD
role: Principal Investigator
affiliation: National Taiwan University Hospital
last name: Tung-Hung Su, MD, PhD
phone: 886972651694
email: tunghungsu@gmail.com
last name: Pei-Ying Yang, MS
phone: 886965277228
email: pying0208@gmail.com
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
country: Taiwan
responsible party type: Sponsor
mesh term: Hepatitis A
mesh term: Hepatitis B
mesh term: Hepatitis B, Chronic
mesh term: Hepatitis
mesh term: Hepatitis, Chronic
mesh term: Tenofovir
sharing ipd: No