<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/NCT01732367</url>
  </required_header>
  <id_info>
    <org_study_id>TDF0001</org_study_id>
    <nct_id>NCT01732367</nct_id>
  </id_info>
  <brief_title>TDF VS LAM + ADV in LAM + ADV Treated LAM-resistant CHB Patients With Undetectable Hepatitis B Virus DNA</brief_title>
  <official_title>Randomized Trial of Tenofovir Versus Lamivudine Plus Adefovir in Lamivudine Plus Adefovir Treated Lamivudine-resistant Chronic Hepatitis B Patients With Undetectable Hepatitis B Virus DNA.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Keimyung University Dongsan Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Kyungpook National University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Daegu Catholic University Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>DongGuk University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Pusan National University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Yeungnam University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Keimyung University Dongsan Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will provide a rationale for switch from lamivudine plus adefovir to tenofovir&#xD;
      monotherapy in Lamivudine plus Adefovir Treated Lamivudine-resistant chronic hepatitis B&#xD;
      patients with Undetectable Hepatitis B Virus DNA&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Recently, in Korea, long-term medication of antiviral agents and their resulting resistance&#xD;
      expression have been the most serious cause of failure to treat chronic hepatitis B. Exp.&#xD;
&#xD;
      In particular, the annual resistance rate to lamivudine currently widely being used in Korea&#xD;
      amounts to about 15 to 20 percents and the rate is expected to reach 70 to 80 percent in four&#xD;
      to five years.&#xD;
&#xD;
      The guidelines by the American Association for the Study of Liver Disease (AASLD) and the&#xD;
      European Association for the Study of the Liver (EASL) recommend a combination therapy with&#xD;
      adefovir or tenofovir for patients with lamivudine resistant HBV .&#xD;
&#xD;
      In Korea, however, in case of combined prescription of lamivudine and adefovir, only one of&#xD;
      them is covered by the health insurance and therefore many patients are difficult to continue&#xD;
      treatment due to their economic conditions.&#xD;
&#xD;
      Tenofovir that has been developed most recently and will be placed on sale sooner or later in&#xD;
      Korea has strong antiviral effects, causes little or no emergence of resistant viruses, and&#xD;
      is known to have lower nephrotoxicity than adefovir.&#xD;
&#xD;
      In particular, several papers reported that tenofovir has effective and sustaining antiviral&#xD;
      effects in patients who had other antiviral agents resistant HBV as well as those who&#xD;
      received initial treatment. This shows that patients only with lamivudine resistant HBV can&#xD;
      be treated only with tenofovir without a combination therapy and when they have low levels of&#xD;
      HBV DNA, treatment is relatively effective despite their resistance to adefovir.&#xD;
&#xD;
      Therefore, it is considered that tenofovir switching therapy in patients with undetectable&#xD;
      HBV DNA after lamivudine plus adefovir combination therapy to maintain their virus response.&#xD;
&#xD;
      The results of this study will provide a rationale for switch from lamivudine plus adefovir&#xD;
      to tenofovir monotherapy in such patients.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2012</start_date>
  <completion_date type="Actual">April 2016</completion_date>
  <primary_completion_date type="Actual">March 2016</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage number of patients with virus reactivation</measure>
    <time_frame>Week 96 while on treatment</time_frame>
    <description>Percentage number of patients with virus reactivation (HBV DNA &gt; 40 IU/mL on two consecutive samples taken 1 month apart, or persistent HBV DNA levels of 20-40 IU/mL on three consecutive 1 month interval) at Week 96 while on treatment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Virologic response</measure>
    <time_frame>Week 96 while on treatment</time_frame>
    <description>Virologic response Percentage number of patients with virus reactivation at Week 48</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Antiviral resistance</measure>
    <time_frame>Week 96 while on treatment</time_frame>
    <description>Antiviral resistance percentage number of patients who developed drug resistant mutation at Week 48 and 96 while on randomized therapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biochemical response</measure>
    <time_frame>Week 96 while on treatment</time_frame>
    <description>Biochemical response percentage number of patients with biochemical breakthrough at Week 48 and 96</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serologic response</measure>
    <time_frame>Week 96 while on treatment</time_frame>
    <description>Serologic response (1) HBeAg loss/seroconversion in HBeAg-positive CHB Percentage number of patients with HBeAg loss or seroconversion at Week 48 and 96.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety assessment</measure>
    <time_frame>Week 96 while on treatment</time_frame>
    <description>Safety assessment</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">171</enrollment>
  <condition>Chronic Hepatitis B</condition>
  <arm_group>
    <arm_group_label>Lamivudine plus adefovir</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Continue lamivudine/adefovir add on treatment (standard treatment)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Tenofovir</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Switch from lamivudine/adefovir add on treatment to tenofovir monotherapy</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lamivudine plus adefovir</intervention_name>
    <description>Lamivudine 100mg QD for 96 weeks + Adefovir 10mg QD for 96 weeks</description>
    <arm_group_label>Lamivudine plus adefovir</arm_group_label>
    <other_name>Zeffix</other_name>
    <other_name>Hepsera</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tenofovir</intervention_name>
    <description>Tenofovir 300mg QD for 96 weeks</description>
    <arm_group_label>Tenofovir</arm_group_label>
    <other_name>Viread</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male and female patients aged 18 or older&#xD;
&#xD;
          -  The CHB patients (both HBeAg-positive and - negative) who have at least 6 months&#xD;
             undetectable HBV DNA (serum HBV DNA ≤ 20 IU/mL) after lamivudine plus adefovir&#xD;
             combination therapy.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with decompensated liver disease&#xD;
&#xD;
          -  Patients with HCV, HDV or HIV&#xD;
&#xD;
          -  Patients with HCC&#xD;
&#xD;
          -  Serum ALT &gt; 2x ULN level&#xD;
&#xD;
          -  Serum creatinine &gt; 2.0mg/dL&#xD;
&#xD;
          -  Pregnant or lactating women&#xD;
&#xD;
          -  Women who have a plan for pregnancy within the three coming years&#xD;
&#xD;
          -  Patients who have uncontrolled severe concomitant diseases- severe cardiovascular&#xD;
             diseases and other infection&#xD;
&#xD;
          -  Those who have no capabilities to understand and sign an informed consent&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Byoung Kuk Jang, M.D</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of Internal Medicine, Keimyung University Dongsan Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Internal Medicine, Keimyung University Dongsan Medical Center</name>
      <address>
        <city>Daegu</city>
        <zip>ASI|KR|KS002|TAEGU</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <verification_date>October 2016</verification_date>
  <study_first_submitted>November 19, 2012</study_first_submitted>
  <study_first_submitted_qc>November 21, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 22, 2012</study_first_posted>
  <last_update_submitted>October 27, 2016</last_update_submitted>
  <last_update_submitted_qc>October 27, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 28, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Keimyung University Dongsan Medical Center</investigator_affiliation>
    <investigator_full_name>Jang Byoung Kuk</investigator_full_name>
    <investigator_title>Keimyung University Dongsan Medical Center</investigator_title>
  </responsible_party>
  <keyword>Tenofovir</keyword>
  <keyword>Lamivudine</keyword>
  <keyword>Adefovir</keyword>
  <keyword>Chronic Hepatitis B</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>
    <mesh_term>Lamivudine</mesh_term>
    <mesh_term>Adefovir</mesh_term>
  </intervention_browse>
  <!-- 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/NCT01732367
org study id: TDF0001
nct id: NCT01732367
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
This study will provide a rationale for switch from lamivudine plus adefovir to tenofovir
      monotherapy in Lamivudine plus Adefovir Treated Lamivudine-resistant chronic hepatitis B
      patients with Undetectable Hepatitis B Virus DNA
Recently, in Korea, long-term medication of antiviral agents and their resulting resistance
      expression have been the most serious cause of failure to treat chronic hepatitis B. Exp.

      In particular, the annual resistance rate to lamivudine currently widely being used in Korea
      amounts to about 15 to 20 percents and the rate is expected to reach 70 to 80 percent in four
      to five years.

      The guidelines by the American Association for the Study of Liver Disease (AASLD) and the
      European Association for the Study of the Liver (EASL) recommend a combination therapy with
      adefovir or tenofovir for patients with lamivudine resistant HBV .

      In Korea, however, in case of combined prescription of lamivudine and adefovir, only one of
      them is covered by the health insurance and therefore many patients are difficult to continue
      treatment due to their economic conditions.

      Tenofovir that has been developed most recently and will be placed on sale sooner or later in
      Korea has strong antiviral effects, causes little or no emergence of resistant viruses, and
      is known to have lower nephrotoxicity than adefovir.

      In particular, several papers reported that tenofovir has effective and sustaining antiviral
      effects in patients who had other antiviral agents resistant HBV as well as those who
      received initial treatment. This shows that patients only with lamivudine resistant HBV can
      be treated only with tenofovir without a combination therapy and when they have low levels of
      HBV DNA, treatment is relatively effective despite their resistance to adefovir.

      Therefore, it is considered that tenofovir switching therapy in patients with undetectable
      HBV DNA after lamivudine plus adefovir combination therapy to maintain their virus response.

      The results of this study will provide a rationale for switch from lamivudine plus adefovir
      to tenofovir monotherapy in such patients.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Percentage number of patients with virus reactivation
time frame: Week 96 while on treatment
description: Percentage number of patients with virus reactivation (HBV DNA > 40 IU/mL on two consecutive samples taken 1 month apart, or persistent HBV DNA levels of 20-40 IU/mL on three consecutive 1 month interval) at Week 96 while on treatment.
measure: Virologic response
time frame: Week 96 while on treatment
description: Virologic response Percentage number of patients with virus reactivation at Week 48
measure: Antiviral resistance
time frame: Week 96 while on treatment
description: Antiviral resistance percentage number of patients who developed drug resistant mutation at Week 48 and 96 while on randomized therapy.
measure: Biochemical response
time frame: Week 96 while on treatment
description: Biochemical response percentage number of patients with biochemical breakthrough at Week 48 and 96
measure: Serologic response
time frame: Week 96 while on treatment
description: Serologic response (1) HBeAg loss/seroconversion in HBeAg-positive CHB Percentage number of patients with HBeAg loss or seroconversion at Week 48 and 96.
measure: Safety assessment
time frame: Week 96 while on treatment
description: Safety assessment
arm group label: Lamivudine plus adefovir
arm group type: Active Comparator
description: Continue lamivudine/adefovir add on treatment (standard treatment)
arm group label: Tenofovir
arm group type: Experimental
description: Switch from lamivudine/adefovir add on treatment to tenofovir monotherapy
intervention type: Drug
intervention name: Lamivudine plus adefovir
description: Lamivudine 100mg QD for 96 weeks + Adefovir 10mg QD for 96 weeks
arm group label: Lamivudine plus adefovir
other name: Zeffix
other name: Hepsera
intervention type: Drug
intervention name: Tenofovir
description: Tenofovir 300mg QD for 96 weeks
arm group label: Tenofovir
other name: Viread
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Byoung Kuk Jang, M.D
role: Principal Investigator
affiliation: Department of Internal Medicine, Keimyung University Dongsan Medical Center
facility: 
country: Korea, Republic of
responsible party type: Principal Investigator
investigator affiliation: Keimyung University Dongsan Medical Center
investigator full name: Jang Byoung Kuk
investigator title: Keimyung University Dongsan Medical Center
mesh term: Hepatitis A
mesh term: Hepatitis B
mesh term: Hepatitis B, Chronic
mesh term: Hepatitis
mesh term: Hepatitis, Chronic
mesh term: Tenofovir
mesh term: Lamivudine
mesh term: Adefovir