<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/NCT03753074</url>
  </required_header>
  <id_info>
    <org_study_id>IN-KR-320-5358</org_study_id>
    <nct_id>NCT03753074</nct_id>
  </id_info>
  <brief_title>Effectiveness of TAF in Reducing Clinical Events in CHB Patients Beyond Treatment Indications by Current Guidelines</brief_title>
  <acronym>ATTENTION</acronym>
  <official_title>A Multinational, Multicenter, Open-label, Randomized Controlled Trial to Investigate the Effectiveness of Tenofovir Alafenamide in Reducing Clinical Events in Chronic Hepatitis B Patients Beyond Treatment Indications by Current Guidelines</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Young-Suk Lim</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Samsung Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Kyunghee University Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Chung-Ang University Hosptial, Chung-Ang University College of Medicine</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Seoul National University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Ulsan University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Konkuk University Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Kyungpook National University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Korea University Guro Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Seoul St. Mary's Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Kaohsiung Medical University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Chang Gung Memorial Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>E-DA Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Taitung Mackay Memorial Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Cheng-Kung University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Chi Mei Medical Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Chiayi Christian Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>St. Martin De Porress Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Dalin Tzu Chi General Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Taichung Veterans General Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>China Medical University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Asan Medical Center</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      Treatment with Tenofovir Alafenamide(TAF) in Chronic Hepatitis B (CHB) patients classified as&#xD;
      beyond treatment indication of current international guidelines (e.g. aged more than 40 years&#xD;
      old and 4 ≤ log HBV-DNA IU/mL &lt; 8) is expected to bring improvement in long-term clinical&#xD;
      outcomes. This expected result may expand the treatment indications in patients with CHB&#xD;
      based on age and HBV-DNA in contrast to current international guidelines of CHB.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study objectives: To investigate whether TAF treatment reduce clinical events (HCC, death,&#xD;
      liver decompensation, portal hypertensive complications, and liver transplantation) in CHB&#xD;
      patients beyond treatment indications by current guidelines&#xD;
&#xD;
      Study procedure: 780 subjects will be randomized in a 1:1 ratio (A:B) either to receive TAF&#xD;
      25 mg QD or to receive best supportive care after stratification according to the HBeAg&#xD;
      status.&#xD;
&#xD;
      The duration of maintaining both arms is 8 years. During treatment period, among treatment&#xD;
      arm B, subjects who are indicated for antiviral treatment will be treated with TAF as&#xD;
      follows:&#xD;
&#xD;
        1. Based on the AASLD 2018 Guidelines of CHB (ALT 70≥ for male, 50≥ for female)&#xD;
&#xD;
        2. 40≤ALT levels&lt;70 IU/L (males) or 40≤ ALT levels&lt;50 IU/L (females) with evidence of&#xD;
           significant fibrosis(F2; ≥7.2 kPa) as measured by either liver biopsy, Fibroscan or MR&#xD;
           elastograpy performed within 3 months.&#xD;
&#xD;
        3. If they were clinically judged to have cirrhosis by investigators and confirmed with&#xD;
           Fibroscan (≥ 12.0 kPa).&#xD;
&#xD;
             -  Treatment Arm A: 390 subjects administered TAF 25 mg once daily&#xD;
&#xD;
             -  Treatment Arm B: 390 subjects received best supportive care&#xD;
&#xD;
      The primary analysis will occur at Year 4 with the primary endpoint being cumulative&#xD;
      incidence rate of clinical events&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 18, 2019</start_date>
  <completion_date type="Anticipated">December 31, 2031</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2031</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>Cumulative rate of patients with clinical events</measure>
    <time_frame>At year 4</time_frame>
    <description>Cumulative rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cumulative and annual rate of patients with clinical events</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Cumulative rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative and annual incidence rate of HCC</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Cumulative incidence rate of HCC</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All-cause mortality</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>All-cause mortality</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative and annual incidence rate of liver transplantation</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Cumulative incidence rate of liver transplantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative and annual incidence rate of liver decompensation</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Cumulative incidence rate of liver decompensation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative and annual incidence rate of portal hypertensive complications</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Cumulative incidence rate of portal hypertensive complications</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of receiving nucleos(t)ide analogue by meeting reimbursement criteria of treatment among Treatment ARM B subjects</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Rate of receiving nucleos(t)ide analogue by meeting reimbursement criteria of treatment among Treatment ARM B subjects</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Virologic response defined as HBV DNA less than 15 IU/mL</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Virologic response defined as HBV DNA less than 15 IU/mL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of ALT normalization</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Rate of ALT normalization if baseline ALT is elevated</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of HBeAg seroclearance and seroconversion</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Rate of HBeAg seroclearance and seroconversion among HBeAg-positive patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of fibroscan</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Change of fibroscan</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of APRI index</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Change of APRI index</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of FIB-4</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Change of FIB-4</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative and annual incidence rate of HCC among HBeAg-positive or HBeAg-negative Patients</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Cumulative incidence rate of HCC among HBeAg-positive or HBeAg-negative Patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All cause-mortality among HBeAg-positive or HBeAg-negative</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>All cause-mortality among HBeAg-positive or HBeAg-negative</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative and annual incidence rate of liver transplantation among HBeAg-positive or HBeAg-negative</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Cumulative incidence rate of liver transplantation among HBeAg-positive or HBeAg-negative</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative and annual incidence rate of liver decompensation among HBeAg-positive or HBeAg-negative</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Cumulative incidence rate of liver decompensation among HBeAg-positive or HBeAg-negative</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative and annual incidence rate of portal hypertensive complications among HBeAg-positive or HBeAg-negative</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Cumulative incidence rate of portal hypertensive complications amongHBeAg-positive or HBeAg-negative</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative and annual incidence rate of HCC among subjects according to baseline ALT level (normal ALT and elevated ALT)</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Cumulative incidence rate of HCC amongsubjects according to baseline ALT level (normal ALT and elevated ALT)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All cause-mortality among subjects according to baseline ALT level (normal ALT and elevated ALT)</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>All cause-mortality among subjects according to baseline ALT level (normal ALT and elevated ALT)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative and annual incidence rate of liver transplantation among subjects according to baseline ALT level (normal ALT and elevated ALT)</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Cumulative incidence rate of liver transplantation among subjects according to baseline ALT level (normal ALT and elevated ALT)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative and annual incidence rate of liver decompensation among subjects according to baseline ALT level (normal ALT and elevated ALT)</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Cumulative incidence rate of liver decompensation among subjects according to baseline ALT level (normal ALT and elevated ALT)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative and annual incidence rate of portal hypertensive complications among subjects according to baseline ALT level (normal ALT and elevated ALT)</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Cumulative incidence rate of portal hypertensive complications among subjects according to baseline ALT level (normal ALT and elevated ALT)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative and annual rate of patients with clinical events</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) after excluding patients who occurrs clinical events within 6 months of enrollment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative and annual rate of patients with clinical events</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) after excluding patients who occurrs clinical events within 12 months of enrollment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative and annual rate of patients with clinical events</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) in patients with normal ALT (&lt;40 U/L) at the time of enrollment, after excluding patients who occurrs clinical events within 6 months of enrollment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative and annual rate of patients with clinical events</measure>
    <time_frame>At year 4 and 8</time_frame>
    <description>Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) in patients with normal ALT (&lt;40 U/L) at the time of enrollment, after excluding patients who occurrs clinical events within 12 months of enrollment</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">780</enrollment>
  <condition>Chronic Hepatitis b</condition>
  <arm_group>
    <arm_group_label>Treatment Arm A (TAF)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>390 subjects administered Tenofovir Alafenamide 25 mg once daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment Arm B (Best supportive care)</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>390 subjects received best supportive care&#xD;
During treatment period, among treatment arm B, subjects who are indicated for antiviral treatment will be treated with TAF as follows:&#xD;
Based on the AASLD 2018 Guidelines of CHB (ALT 70≥ for male, 50≥ for female)&#xD;
40≤ALT levels&lt;70 IU/L (males) or 40≤ ALT levels&lt;50 IU/L (females) with evidence of significant fibrosis(F2; ≥7.2 kPa) as measured by either liver biopsy, Fibroscan or MR elastograpy performed within 3 months.&#xD;
If they were clinically judged to have cirrhosis by investigators and confirmed with Fibroscan (≥ 12.0 kPa).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tenofovir Alafenamide</intervention_name>
    <description>Tenofovir Alafenamide 25mg, Tablet, Oral, Daily</description>
    <arm_group_label>Treatment Arm A (TAF)</arm_group_label>
    <other_name>Vemlidy</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria: Patients must meet all of the following criteria to be eligible to&#xD;
        participate in the study&#xD;
&#xD;
          1. Patient must have the ability to understand and sign a written informed consent form;&#xD;
             consent must be obtained prior to initiation of study procedures&#xD;
&#xD;
          2. Male or female, 40 to 80 years of age&#xD;
&#xD;
          3. Positive for HBsAg or HBV DNA for at least 6 months or more&#xD;
&#xD;
          4. HBeAg positive or negative&#xD;
&#xD;
          5. No evidence of liver cirrhosis (platelet count ≥100,000/mm3)&#xD;
&#xD;
          6. serum HBV DNA ≥ 4 log10 IU/mL and ≤ 8 log10 IU/mL&#xD;
&#xD;
          7. Serum ALT level &lt;70 if male, &lt;50 if female&#xD;
&#xD;
          8. Estimated creatinine clearance ≥ 30 ml/min based on serum creatinine as measured at&#xD;
             the screening evaluation&#xD;
&#xD;
          9. Patient is willing and able to comply with all study requirements&#xD;
&#xD;
        Exclusion Criteria: Patients who meet any of the following exclusion criteria are not to be&#xD;
        enrolled in this study&#xD;
&#xD;
          1. Co-infection with HCV, HDV, HIV (Confirmed by nucleic acid tests)&#xD;
&#xD;
          2. Abusing alcohol (more than 60 g/day) or illicit drugs&#xD;
&#xD;
          3. Patients with history of hepatic decompensation (e.g., ascites, encephalopathy or&#xD;
             variceal hemorrhage)&#xD;
&#xD;
        4-1) Evidence of cirrhosis, including any of follows:&#xD;
&#xD;
          1. Platelet count &lt;100,000/mm3&#xD;
&#xD;
          2. Esophagogastric varices on endoscopy&#xD;
&#xD;
          3. Evidence of clinically significant portal hypertension&#xD;
&#xD;
          4. Fibroscan ≥ 12.0 kPa (If the test was done in 3 months before the time of screening.)&#xD;
             and confirmed to have liver cirrhosis by an investigator&#xD;
&#xD;
        4-2) 40≤ALT levels&lt;70 IU/L (males) or 40≤ ALT levels&lt;50 IU/L (females) with evidence of&#xD;
        significant fibrosis(F2; ≥7.2 kPa) as measured by either liver biopsy, Fibroscan or MR&#xD;
        elastograpy performed within 3 months.&#xD;
&#xD;
        5. Received interferon or other immunomodulatory treatment for HBV infection in the 12&#xD;
        months before screening for this study&#xD;
&#xD;
        6. Medical condition that requires concurrent use of systemic corticosteroid or other&#xD;
        immunosuppressive agents&#xD;
&#xD;
        7. Received solid organ or bone marrow transplant&#xD;
&#xD;
        8. Known hypersensitivity to study drugs, metabolites, or formulation excipients&#xD;
&#xD;
        9. Any other clinical condition or prior therapy that, in the opinion of the Investigator,&#xD;
        would make the patient unsuitable for the study or unable to comply with dosing&#xD;
        requirements&#xD;
&#xD;
        10. Use of investigational agents within 6 months of screening, unless allowed by the&#xD;
        Sponsor or Investigator&#xD;
&#xD;
        11. Significant renal, cardiovascular, pulmonary, or neurological disease in the opinion of&#xD;
        the Investigator&#xD;
&#xD;
        12. Any malignant tumor in the preceding five years. However, a history of treated&#xD;
        malignancy (other than HCC) is allowable if the patient's malignancy has been in complete&#xD;
        remission, off chemotherapy and without additional surgical intervention, during the&#xD;
        preceding three years&#xD;
&#xD;
        13. Pregnant or breastfeeding or willing to be pregnant&#xD;
&#xD;
        14. Participating in other clinical trials to administer medication. However, it is&#xD;
        possible to participate if it is not an antiviral agent or immunosuppressant related&#xD;
        clinical trial.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Young-Suk Lim, M.D, Ph D</last_name>
    <role>Principal Investigator</role>
    <affiliation>Asan Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Young-Suk Lim, M.D, Ph D</last_name>
    <phone>+82-2-3010-5933</phone>
    <email>limys@amc.seoul.kr</email>
  </overall_contact>
  <location>
    <facility>
      <name>Kyungpook National University Hospital</name>
      <address>
        <city>Daegu</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Soo Young Park, PhD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Asan Medical Center</name>
      <address>
        <city>Seoul</city>
        <zip>05505</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Young-Suk Lim, M.D., Ph.D.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Chung-Ang University Hospital</name>
      <address>
        <city>Seoul</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hyung Joon Kim, PhD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Konkuk University Hospital</name>
      <address>
        <city>Seoul</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>So Young Kwon, PhD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Korea University Guro Hospital</name>
      <address>
        <city>Seoul</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ji Hoon Kim, PhD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Kyung-Hee University Hospital</name>
      <address>
        <city>Seoul</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Gi-Ae Kim, PhD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Samsung Medical center</name>
      <address>
        <city>Seoul</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Myung Ji Goh, PhD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Seoul National University Hospital</name>
      <address>
        <city>Seoul</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Yun Bin Lee, PhD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>The Catholic University of Korea, Seoul ST. Mary's Hospital</name>
      <address>
        <city>Seoul</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Withdrawn</status>
  </location>
  <location>
    <facility>
      <name>Ulsan University Hospital</name>
      <address>
        <city>Ulsan</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Neung-Hwa Park, PhD</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <reference>
    <citation>Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr, Bzowej NH, Wong JB. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018 Apr;67(4):1560-1599. doi: 10.1002/hep.29800. No abstract available.</citation>
    <PMID>29405329</PMID>
  </reference>
  <reference>
    <citation>European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017 Aug;67(2):370-398. doi: 10.1016/j.jhep.2017.03.021. Epub 2017 Apr 18.</citation>
    <PMID>28427875</PMID>
  </reference>
  <reference>
    <citation>Tseng TC, Kao JH. Treating Immune-tolerant Hepatitis B. J Viral Hepat. 2015 Feb;22(2):77-84. doi: 10.1111/jvh.12370. Epub 2014 Nov 25.</citation>
    <PMID>25424771</PMID>
  </reference>
  <reference>
    <citation>Andreani T, Serfaty L, Mohand D, Dernaika S, Wendum D, Chazouilleres O, Poupon R. Chronic hepatitis B virus carriers in the immunotolerant phase of infection: histologic findings and outcome. Clin Gastroenterol Hepatol. 2007 May;5(5):636-41. doi: 10.1016/j.cgh.2007.01.005. Epub 2007 Apr 11.</citation>
    <PMID>17428739</PMID>
  </reference>
  <reference>
    <citation>Hui CK, Leung N, Yuen ST, Zhang HY, Leung KW, Lu L, Cheung SK, Wong WM, Lau GK; Hong Kong Liver Fibrosis Study Group. Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase. Hepatology. 2007 Aug;46(2):395-401. doi: 10.1002/hep.21724.</citation>
    <PMID>17628874</PMID>
  </reference>
  <reference>
    <citation>Kennedy PTF, Sandalova E, Jo J, Gill U, Ushiro-Lumb I, Tan AT, Naik S, Foster GR, Bertoletti A. Preserved T-cell function in children and young adults with immune-tolerant chronic hepatitis B. Gastroenterology. 2012 Sep;143(3):637-645. doi: 10.1053/j.gastro.2012.06.009. Epub 2012 Jun 15.</citation>
    <PMID>22710188</PMID>
  </reference>
  <reference>
    <citation>Lai M, Hyatt BJ, Nasser I, Curry M, Afdhal NH. The clinical significance of persistently normal ALT in chronic hepatitis B infection. J Hepatol. 2007 Dec;47(6):760-7. doi: 10.1016/j.jhep.2007.07.022. Epub 2007 Sep 24.</citation>
    <PMID>17928090</PMID>
  </reference>
  <reference>
    <citation>Kumar M, Sarin SK, Hissar S, Pande C, Sakhuja P, Sharma BC, Chauhan R, Bose S. Virologic and histologic features of chronic hepatitis B virus-infected asymptomatic patients with persistently normal ALT. Gastroenterology. 2008 May;134(5):1376-84. doi: 10.1053/j.gastro.2008.02.075. Epub 2008 Feb 29.</citation>
    <PMID>18471514</PMID>
  </reference>
  <reference>
    <citation>Kim GA, Lim YS, Han S, Choi J, Shim JH, Kim KM, Lee HC, Lee YS. High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B. Gut. 2018 May;67(5):945-952. doi: 10.1136/gutjnl-2017-314904. Epub 2017 Oct 21.</citation>
    <PMID>29055908</PMID>
  </reference>
  <reference>
    <citation>Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, Huang GT, Iloeje UH; REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006 Jan 4;295(1):65-73. doi: 10.1001/jama.295.1.65.</citation>
    <PMID>16391218</PMID>
  </reference>
  <reference>
    <citation>Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ; Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-In HBV (the REVEAL-HBV) Study Group. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006 Mar;130(3):678-86. doi: 10.1053/j.gastro.2005.11.016.</citation>
    <PMID>16530509</PMID>
  </reference>
  <reference>
    <citation>Lin ZH, Xin YN, Dong QJ, Wang Q, Jiang XJ, Zhan SH, Sun Y, Xuan SY. Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis. Hepatology. 2011 Mar;53(3):726-36. doi: 10.1002/hep.24105. Epub 2011 Feb 11.</citation>
    <PMID>21319189</PMID>
  </reference>
  <reference>
    <citation>Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, S Sulkowski M, Torriani FJ, Dieterich DT, Thomas DL, Messinger D, Nelson M; APRICOT Clinical Investigators. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006 Jun;43(6):1317-25. doi: 10.1002/hep.21178.</citation>
    <PMID>16729309</PMID>
  </reference>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>November 22, 2018</study_first_submitted>
  <study_first_submitted_qc>November 22, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 26, 2018</study_first_posted>
  <last_update_submitted>July 3, 2023</last_update_submitted>
  <last_update_submitted_qc>July 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Asan Medical Center</investigator_affiliation>
    <investigator_full_name>Young-Suk Lim</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <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/NCT03753074
org study id: IN-KR-320-5358
nct id: NCT03753074
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has dmc: No
is fda regulated drug: No
is fda regulated device: No
Treatment with Tenofovir Alafenamide(TAF) in Chronic Hepatitis B (CHB) patients classified as
      beyond treatment indication of current international guidelines (e.g. aged more than 40 years
      old and 4 ≤ log HBV-DNA IU/mL < 8) is expected to bring improvement in long-term clinical
      outcomes. This expected result may expand the treatment indications in patients with CHB
      based on age and HBV-DNA in contrast to current international guidelines of CHB.
Study objectives: To investigate whether TAF treatment reduce clinical events (HCC, death,
      liver decompensation, portal hypertensive complications, and liver transplantation) in CHB
      patients beyond treatment indications by current guidelines

      Study procedure: 780 subjects will be randomized in a 1:1 ratio (A:B) either to receive TAF
      25 mg QD or to receive best supportive care after stratification according to the HBeAg
      status.

      The duration of maintaining both arms is 8 years. During treatment period, among treatment
      arm B, subjects who are indicated for antiviral treatment will be treated with TAF as
      follows:

        1. Based on the AASLD 2018 Guidelines of CHB (ALT 70≥ for male, 50≥ for female)

        2. 40≤ALT levels<70 IU/L (males) or 40≤ ALT levels<50 IU/L (females) with evidence of
           significant fibrosis(F2; ≥7.2 kPa) as measured by either liver biopsy, Fibroscan or MR
           elastograpy performed within 3 months.

        3. If they were clinically judged to have cirrhosis by investigators and confirmed with
           Fibroscan (≥ 12.0 kPa).

             -  Treatment Arm A: 390 subjects administered TAF 25 mg once daily

             -  Treatment Arm B: 390 subjects received best supportive care

      The primary analysis will occur at Year 4 with the primary endpoint being cumulative
      incidence rate of clinical events
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Cumulative rate of patients with clinical events
time frame: At year 4
description: Cumulative rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC)
measure: Cumulative and annual rate of patients with clinical events
time frame: At year 4 and 8
description: Cumulative rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC)
measure: Cumulative and annual incidence rate of HCC
time frame: At year 4 and 8
description: Cumulative incidence rate of HCC
measure: All-cause mortality
time frame: At year 4 and 8
description: All-cause mortality
measure: Cumulative and annual incidence rate of liver transplantation
time frame: At year 4 and 8
description: Cumulative incidence rate of liver transplantation
measure: Cumulative and annual incidence rate of liver decompensation
time frame: At year 4 and 8
description: Cumulative incidence rate of liver decompensation
measure: Cumulative and annual incidence rate of portal hypertensive complications
time frame: At year 4 and 8
description: Cumulative incidence rate of portal hypertensive complications
measure: Rate of receiving nucleos(t)ide analogue by meeting reimbursement criteria of treatment among Treatment ARM B subjects
time frame: At year 4 and 8
description: Rate of receiving nucleos(t)ide analogue by meeting reimbursement criteria of treatment among Treatment ARM B subjects
measure: Virologic response defined as HBV DNA less than 15 IU/mL
time frame: At year 4 and 8
description: Virologic response defined as HBV DNA less than 15 IU/mL
measure: Rate of ALT normalization
time frame: At year 4 and 8
description: Rate of ALT normalization if baseline ALT is elevated
measure: Rate of HBeAg seroclearance and seroconversion
time frame: At year 4 and 8
description: Rate of HBeAg seroclearance and seroconversion among HBeAg-positive patients
measure: Change of fibroscan
time frame: At year 4 and 8
description: Change of fibroscan
measure: Change of APRI index
time frame: At year 4 and 8
description: Change of APRI index
measure: Change of FIB-4
time frame: At year 4 and 8
description: Change of FIB-4
measure: Cumulative and annual incidence rate of HCC among HBeAg-positive or HBeAg-negative Patients
time frame: At year 4 and 8
description: Cumulative incidence rate of HCC among HBeAg-positive or HBeAg-negative Patients
measure: All cause-mortality among HBeAg-positive or HBeAg-negative
time frame: At year 4 and 8
description: All cause-mortality among HBeAg-positive or HBeAg-negative
measure: Cumulative and annual incidence rate of liver transplantation among HBeAg-positive or HBeAg-negative
time frame: At year 4 and 8
description: Cumulative incidence rate of liver transplantation among HBeAg-positive or HBeAg-negative
measure: Cumulative and annual incidence rate of liver decompensation among HBeAg-positive or HBeAg-negative
time frame: At year 4 and 8
description: Cumulative incidence rate of liver decompensation among HBeAg-positive or HBeAg-negative
measure: Cumulative and annual incidence rate of portal hypertensive complications among HBeAg-positive or HBeAg-negative
time frame: At year 4 and 8
description: Cumulative incidence rate of portal hypertensive complications amongHBeAg-positive or HBeAg-negative
measure: Cumulative and annual incidence rate of HCC among subjects according to baseline ALT level (normal ALT and elevated ALT)
time frame: At year 4 and 8
description: Cumulative incidence rate of HCC amongsubjects according to baseline ALT level (normal ALT and elevated ALT)
measure: All cause-mortality among subjects according to baseline ALT level (normal ALT and elevated ALT)
time frame: At year 4 and 8
description: All cause-mortality among subjects according to baseline ALT level (normal ALT and elevated ALT)
measure: Cumulative and annual incidence rate of liver transplantation among subjects according to baseline ALT level (normal ALT and elevated ALT)
time frame: At year 4 and 8
description: Cumulative incidence rate of liver transplantation among subjects according to baseline ALT level (normal ALT and elevated ALT)
measure: Cumulative and annual incidence rate of liver decompensation among subjects according to baseline ALT level (normal ALT and elevated ALT)
time frame: At year 4 and 8
description: Cumulative incidence rate of liver decompensation among subjects according to baseline ALT level (normal ALT and elevated ALT)
measure: Cumulative and annual incidence rate of portal hypertensive complications among subjects according to baseline ALT level (normal ALT and elevated ALT)
time frame: At year 4 and 8
description: Cumulative incidence rate of portal hypertensive complications among subjects according to baseline ALT level (normal ALT and elevated ALT)
measure: Cumulative and annual rate of patients with clinical events
time frame: At year 4 and 8
description: Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) after excluding patients who occurrs clinical events within 6 months of enrollment
measure: Cumulative and annual rate of patients with clinical events
time frame: At year 4 and 8
description: Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) after excluding patients who occurrs clinical events within 12 months of enrollment
measure: Cumulative and annual rate of patients with clinical events
time frame: At year 4 and 8
description: Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) in patients with normal ALT (<40 U/L) at the time of enrollment, after excluding patients who occurrs clinical events within 6 months of enrollment
measure: Cumulative and annual rate of patients with clinical events
time frame: At year 4 and 8
description: Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) in patients with normal ALT (<40 U/L) at the time of enrollment, after excluding patients who occurrs clinical events within 12 months of enrollment
arm group label: Treatment Arm A (TAF)
arm group type: Experimental
description: 390 subjects administered Tenofovir Alafenamide 25 mg once daily
arm group label: Treatment Arm B (Best supportive care)
arm group type: No Intervention
description: 390 subjects received best supportive care
During treatment period, among treatment arm B, subjects who are indicated for antiviral treatment will be treated with TAF as follows:
Based on the AASLD 2018 Guidelines of CHB (ALT 70≥ for male, 50≥ for female)
40≤ALT levels<70 IU/L (males) or 40≤ ALT levels<50 IU/L (females) with evidence of significant fibrosis(F2; ≥7.2 kPa) as measured by either liver biopsy, Fibroscan or MR elastograpy performed within 3 months.
If they were clinically judged to have cirrhosis by investigators and confirmed with Fibroscan (≥ 12.0 kPa).
intervention type: Drug
intervention name: Tenofovir Alafenamide
description: Tenofovir Alafenamide 25mg, Tablet, Oral, Daily
arm group label: Treatment Arm A (TAF)
other name: Vemlidy
criteria: 
gender: All
minimum age: 40 Years
maximum age: 80 Years
healthy volunteers: No
last name: Young-Suk Lim, M.D, Ph D
role: Principal Investigator
affiliation: Asan Medical Center
last name: Young-Suk Lim, M.D, Ph D
phone: +82-2-3010-5933
email: limys@amc.seoul.kr
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Withdrawn
facility: 
status: Recruiting
contact: 
country: Korea, Republic of
citation: Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr, Bzowej NH, Wong JB. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018 Apr;67(4):1560-1599. doi: 10.1002/hep.29800. No abstract available.
PMID: 29405329
citation: European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017 Aug;67(2):370-398. doi: 10.1016/j.jhep.2017.03.021. Epub 2017 Apr 18.
PMID: 28427875
citation: Tseng TC, Kao JH. Treating Immune-tolerant Hepatitis B. J Viral Hepat. 2015 Feb;22(2):77-84. doi: 10.1111/jvh.12370. Epub 2014 Nov 25.
PMID: 25424771
citation: Andreani T, Serfaty L, Mohand D, Dernaika S, Wendum D, Chazouilleres O, Poupon R. Chronic hepatitis B virus carriers in the immunotolerant phase of infection: histologic findings and outcome. Clin Gastroenterol Hepatol. 2007 May;5(5):636-41. doi: 10.1016/j.cgh.2007.01.005. Epub 2007 Apr 11.
PMID: 17428739
citation: Hui CK, Leung N, Yuen ST, Zhang HY, Leung KW, Lu L, Cheung SK, Wong WM, Lau GK; Hong Kong Liver Fibrosis Study Group. Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase. Hepatology. 2007 Aug;46(2):395-401. doi: 10.1002/hep.21724.
PMID: 17628874
citation: Kennedy PTF, Sandalova E, Jo J, Gill U, Ushiro-Lumb I, Tan AT, Naik S, Foster GR, Bertoletti A. Preserved T-cell function in children and young adults with immune-tolerant chronic hepatitis B. Gastroenterology. 2012 Sep;143(3):637-645. doi: 10.1053/j.gastro.2012.06.009. Epub 2012 Jun 15.
PMID: 22710188
citation: Lai M, Hyatt BJ, Nasser I, Curry M, Afdhal NH. The clinical significance of persistently normal ALT in chronic hepatitis B infection. J Hepatol. 2007 Dec;47(6):760-7. doi: 10.1016/j.jhep.2007.07.022. Epub 2007 Sep 24.
PMID: 17928090
citation: Kumar M, Sarin SK, Hissar S, Pande C, Sakhuja P, Sharma BC, Chauhan R, Bose S. Virologic and histologic features of chronic hepatitis B virus-infected asymptomatic patients with persistently normal ALT. Gastroenterology. 2008 May;134(5):1376-84. doi: 10.1053/j.gastro.2008.02.075. Epub 2008 Feb 29.
PMID: 18471514
citation: Kim GA, Lim YS, Han S, Choi J, Shim JH, Kim KM, Lee HC, Lee YS. High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B. Gut. 2018 May;67(5):945-952. doi: 10.1136/gutjnl-2017-314904. Epub 2017 Oct 21.
PMID: 29055908
citation: Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, Huang GT, Iloeje UH; REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006 Jan 4;295(1):65-73. doi: 10.1001/jama.295.1.65.
PMID: 16391218
citation: Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ; Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-In HBV (the REVEAL-HBV) Study Group. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006 Mar;130(3):678-86. doi: 10.1053/j.gastro.2005.11.016.
PMID: 16530509
citation: Lin ZH, Xin YN, Dong QJ, Wang Q, Jiang XJ, Zhan SH, Sun Y, Xuan SY. Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis. Hepatology. 2011 Mar;53(3):726-36. doi: 10.1002/hep.24105. Epub 2011 Feb 11.
PMID: 21319189
citation: Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, S Sulkowski M, Torriani FJ, Dieterich DT, Thomas DL, Messinger D, Nelson M; APRICOT Clinical Investigators. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006 Jun;43(6):1317-25. doi: 10.1002/hep.21178.
PMID: 16729309
responsible party type: Sponsor-Investigator
investigator affiliation: Asan Medical Center
investigator full name: Young-Suk Lim
investigator title: Professor
mesh term: Hepatitis B
mesh term: Hepatitis B, Chronic
mesh term: Hepatitis
mesh term: Hepatitis, Chronic
mesh term: Tenofovir
sharing ipd: No