xml: <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/NCT06041022</url>
    </required_header>
    <id_info>
      <org_study_id>KYLL-202301-030</org_study_id>
      <nct_id>NCT06041022</nct_id>
    </id_info>
    <brief_title>A Non-invasive Model to Predict Antiviral Therapy in Gray Zone of Chronic Hepatitis B</brief_title>
    <official_title>A Non-invasive Model to Predict Antiviral Therapy in Patients With Gray Zone of Chronic Hepatitis B: a Multi-center, Retrospective Study</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Qilu Hospital of Shandong University</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Linyi People's Hospital</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>First Affiliated Hospital Xi'an Jiaotong University</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>First Affiliated Hospital of Wenzhou Medical University</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Third Affiliated Hospital, Sun Yat-Sen University</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Sir Run Run Shaw Hospital</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>First Affiliated Hospital of Zhejiang University</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Qilu Hospital of Shandong University</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>
        Establishment and validation of the non-invasive model to predict antiviral therapy in the&#xD;
        gray zone of chronic hepatitis B&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Chronic hepatitis B virus (HBV) infection continues to be a major public health problem&#xD;
        worldwide today. According to statistics, the prevalence of chronic HBV infection assessed&#xD;
        globally in 2016 was 3.5%, or 257 million people with chronic infection. In China, it is&#xD;
        estimated that about 70 million people are chronically infected with HBV in 2019, including&#xD;
        about 20-30 million people with chronic hepatitis B (CHB). CHB is a major risk factor for&#xD;
        cirrhosis, and hepatocellular carcinoma (HCC). 12-20% of patients with chronic hepatitis B&#xD;
        will develop cirrhosis, and of these, around 20% will further develop decompensated cirrhosis&#xD;
        and 6-15% will develop HCC, with hepatitis B accounting for approximately 50% of HCC cases&#xD;
        worldwide. Therefore, strongly and exact management of chronic hepatitis B is extremely&#xD;
        important for the control of HBV progression. Current domestic and international clinical&#xD;
        guidelines generally divide the natural history of chronic hepatitis B into four immune&#xD;
        phases based on HBV DNA levels, liver injury, and HBeAg status: immune active, immune&#xD;
        tolerant, inactive HBsAg carriers, and reactive stage. The guidelines of American Association&#xD;
        for the Study of Liver Diseases (AASLD) recommend the use of antiviral therapy for patients&#xD;
        in the immune active and reactive phases, and also provide a detailed follow-up plan for&#xD;
        patients in other phases. However, a significant number of patients with chronic hepatitis B&#xD;
        cannot be classified in any of these four phases, who falls into a gray area with uncertainty&#xD;
        of formal management. According to the 2018 AASLD Hepatitis B Guidelines criteria for&#xD;
        antiviral therapy, patients in the gray zone still do not have clarity on the need for&#xD;
        antiviral therapy based only on clinical indicators. A recent study showed that nearly 40% of&#xD;
        patients with chronic hepatitis B were in the indeterminate stage. At long-term follow-up&#xD;
        assessment, half of these patients were still in the indeterminate phase and one-fifth had&#xD;
        transitioned to the immune active phase. Patients in the indeterminate phase were 14 times&#xD;
        more likely to develop HCC than those with inactive hepatitis B. Therefore, the management of&#xD;
        antiviral therapy in patients with CHB in the &quot;gray zone&quot; is crucial and should be&#xD;
        demonstrated. The aim of the investigators is to investigate the clinical characteristics of&#xD;
        patients with uncertain treatment in the &quot;gray zone&quot; of CHB and to develop a non-invasive&#xD;
        predictive model for the indication of antiviral therapy. This will provide guidance for the&#xD;
        clinical management of patients in the &quot;gray zone&quot; of CHB, thereby reducing the incidence of&#xD;
        cirrhosis and liver cancer and improving their quality of life.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">October 1, 2023</start_date>
    <completion_date type="Anticipated">December 31, 2023</completion_date>
    <primary_completion_date type="Anticipated">November 1, 2023</primary_completion_date>
    <study_type>Observational</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <observational_model>Case-Only</observational_model>
      <time_perspective>Retrospective</time_perspective>
    </study_design_info>
    <primary_outcome>
      <measure>Number of participants with the antiviral therapy as assessed by AASLD guideline</measure>
      <time_frame>From Jan 1st,2010 to Aug 31,2023</time_frame>
      <description>The criteria of antiviral therapy:&#xD;
  Immune-active CHB: an elevation of ALT≥2 the upper limit of normal (ULN)plus elevated HBV DNA above 2,000 IU/mL (HBeAg negative) or above 20,000 IU/mL (HBeAg positive).&#xD;
  Immune-active CHB and cirrhosis if HBV DNA is &gt;2,000 IU/mL.&#xD;
  Immune-active CHB with ALT &lt; 2 the ULN and HBV DNA below thresholds (less than 2,000 IU/mL if HBeAg negative or less than 20,000 IU/mL if HBeAg positive) are as follows: 1) Age: older age (&gt;40 years). 2) Family history of cirrhosis or HCC. 3) Previous treatment history. 4) Presence of extrahepatic manifestations. 5) Presence of cirrhosis.&#xD;
  Immune tolerance CHB with the moderate-to-severe necroinflammation or fibrosis on a liver biopsy specimen.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Number of participants with significant liver histology as assessed by Metavia scoring system</measure>
      <time_frame>From Jan 1st,2010 to Aug 31,2023</time_frame>
      <description>Significant liver histology showing significant hepatic inflammation ≥G2 and/or fibrosis ≥S2 as assessed by Metavir scoring system&#xD;
  The fibrosis score is used to describe the amount of inflammation (the intensity of inflammation/breakdown of tissue) in the liver:&#xD;
  F0: No fibrosis F1: Portal fibrosis without septa F2: Portal fibrosis with few septa F3: Numerous septa without cirrhosis F4: Cirrhosis&#xD;
  The activity score is a prediction about how rapidly the degree of fibrosis is progressing:&#xD;
  G0: No activity G1: Mild activity G2: Moderate activity G3: Severe activity</description>
    </primary_outcome>
    <enrollment type="Anticipated">1000</enrollment>
    <condition>Hepatitis B, Chronic</condition>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Exposure factors</intervention_name>
      <description>Including demographical data, laboratory features and liver histological indicators.</description>
    </intervention>
    <eligibility>
      <study_pop>
        <textblock>
          The minimum sample size required for the study was calculated to be 417, and it was&#xD;
          estimated that almost 1000 patients with chronic hepatitis B underwent hepatic puncture&#xD;
          biopsy in the seven hospitals from 2010 to 2022, and all patients will be included in the&#xD;
          study.&#xD;
        </textblock>
      </study_pop>
      <sampling_method>Non-Probability Sample</sampling_method>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  HBeAg positive, normal serum alanine aminotransferase(ALT) level，HBVDNA≤10^6 IU/ml&#xD;
  &#xD;
            -  HBeAg positive, elevated serum ALT, HBVDNA≤2*10^4 IU/ml&#xD;
  &#xD;
            -  HBeAg negative, elevated serum ALT, HBVDNA≤2*10^3 IU/ml&#xD;
  &#xD;
            -  HBeAg negative, normal serum ALT, HBVDNA≥2*10^3 IU/ml&#xD;
  &#xD;
          Normal upper limit of ALT is 35 U/L for male and 25 U/L for female.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Concurrent with other liver diseases such as autoimmune hepatitis, Hepatitis C virus&#xD;
               infectious, liver cirrhosis, HCC, or unexplained liver function abnormalities&#xD;
  &#xD;
            -  Patients with incomplete clinical data&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>16 Years</minimum_age>
      <maximum_age>65 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Yu-Chen Fan, MD,PhD</last_name>
      <role>Study Chair</role>
      <affiliation>Qilu Hospital of Shandong University</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Yu-Chen Fan, MD,PhD</last_name>
      <phone>18560082065</phone>
      <email>fanyuchen@sdu.edu.cn</email>
    </overall_contact>
    <reference>
      <citation>Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015 Oct 17;386(10003):1546-55. doi: 10.1016/S0140-6736(15)61412-X. Epub 2015 Jul 28.</citation>
      <PMID>26231459</PMID>
    </reference>
    <reference>
      <citation>Wang G, Duan Z. Guidelines for Prevention and Treatment of Chronic Hepatitis B. J Clin Transl Hepatol. 2021 Oct 28;9(5):769-791. doi: 10.14218/JCTH.2021.00209. Epub 2021 Sep 28.</citation>
      <PMID>34722192</PMID>
    </reference>
    <reference>
      <citation>Huang DQ, Lim SG. Hepatitis B: Who to treat? A critical review of international guidelines. Liver Int. 2020 Feb;40 Suppl 1:5-14. doi: 10.1111/liv.14365.</citation>
      <PMID>32077616</PMID>
    </reference>
    <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>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>September 3, 2023</study_first_submitted>
    <study_first_submitted_qc>September 10, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 18, 2023</study_first_posted>
    <last_update_submitted>September 10, 2023</last_update_submitted>
    <last_update_submitted_qc>September 10, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 18, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>Antiviral therapy</keyword>
    <keyword>Liver biopsy</keyword>
    <keyword>Gray zone</keyword>
    <keyword>Model</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>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06041022
  org study id: KYLL-202301-030
  nct id: NCT06041022
  lead sponsor: 
  collaborator: 
  collaborator: 
  collaborator: 
  collaborator: 
  collaborator: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  Establishment and validation of the non-invasive model to predict antiviral therapy in the
        gray zone of chronic hepatitis B
  Chronic hepatitis B virus (HBV) infection continues to be a major public health problem
        worldwide today. According to statistics, the prevalence of chronic HBV infection assessed
        globally in 2016 was 3.5%, or 257 million people with chronic infection. In China, it is
        estimated that about 70 million people are chronically infected with HBV in 2019, including
        about 20-30 million people with chronic hepatitis B (CHB). CHB is a major risk factor for
        cirrhosis, and hepatocellular carcinoma (HCC). 12-20% of patients with chronic hepatitis B
        will develop cirrhosis, and of these, around 20% will further develop decompensated cirrhosis
        and 6-15% will develop HCC, with hepatitis B accounting for approximately 50% of HCC cases
        worldwide. Therefore, strongly and exact management of chronic hepatitis B is extremely
        important for the control of HBV progression. Current domestic and international clinical
        guidelines generally divide the natural history of chronic hepatitis B into four immune
        phases based on HBV DNA levels, liver injury, and HBeAg status: immune active, immune
        tolerant, inactive HBsAg carriers, and reactive stage. The guidelines of American Association
        for the Study of Liver Diseases (AASLD) recommend the use of antiviral therapy for patients
        in the immune active and reactive phases, and also provide a detailed follow-up plan for
        patients in other phases. However, a significant number of patients with chronic hepatitis B
        cannot be classified in any of these four phases, who falls into a gray area with uncertainty
        of formal management. According to the 2018 AASLD Hepatitis B Guidelines criteria for
        antiviral therapy, patients in the gray zone still do not have clarity on the need for
        antiviral therapy based only on clinical indicators. A recent study showed that nearly 40% of
        patients with chronic hepatitis B were in the indeterminate stage. At long-term follow-up
        assessment, half of these patients were still in the indeterminate phase and one-fifth had
        transitioned to the immune active phase. Patients in the indeterminate phase were 14 times
        more likely to develop HCC than those with inactive hepatitis B. Therefore, the management of
        antiviral therapy in patients with CHB in the "gray zone" is crucial and should be
        demonstrated. The aim of the investigators is to investigate the clinical characteristics of
        patients with uncertain treatment in the "gray zone" of CHB and to develop a non-invasive
        predictive model for the indication of antiviral therapy. This will provide guidance for the
        clinical management of patients in the "gray zone" of CHB, thereby reducing the incidence of
        cirrhosis and liver cancer and improving their quality of life.
  observational model: Case-Only
  time perspective: Retrospective
  measure: Number of participants with the antiviral therapy as assessed by AASLD guideline
  time frame: From Jan 1st,2010 to Aug 31,2023
  description: The criteria of antiviral therapy:
  Immune-active CHB: an elevation of ALT≥2 the upper limit of normal (ULN)plus elevated HBV DNA above 2,000 IU/mL (HBeAg negative) or above 20,000 IU/mL (HBeAg positive).
  Immune-active CHB and cirrhosis if HBV DNA is >2,000 IU/mL.
  Immune-active CHB with ALT < 2 the ULN and HBV DNA below thresholds (less than 2,000 IU/mL if HBeAg negative or less than 20,000 IU/mL if HBeAg positive) are as follows: 1) Age: older age (>40 years). 2) Family history of cirrhosis or HCC. 3) Previous treatment history. 4) Presence of extrahepatic manifestations. 5) Presence of cirrhosis.
  Immune tolerance CHB with the moderate-to-severe necroinflammation or fibrosis on a liver biopsy specimen.
  measure: Number of participants with significant liver histology as assessed by Metavia scoring system
  time frame: From Jan 1st,2010 to Aug 31,2023
  description: Significant liver histology showing significant hepatic inflammation ≥G2 and/or fibrosis ≥S2 as assessed by Metavir scoring system
  The fibrosis score is used to describe the amount of inflammation (the intensity of inflammation/breakdown of tissue) in the liver:
  F0: No fibrosis F1: Portal fibrosis without septa F2: Portal fibrosis with few septa F3: Numerous septa without cirrhosis F4: Cirrhosis
  The activity score is a prediction about how rapidly the degree of fibrosis is progressing:
  G0: No activity G1: Mild activity G2: Moderate activity G3: Severe activity
  intervention type: Other
  intervention name: Exposure factors
  description: Including demographical data, laboratory features and liver histological indicators.
  study pop: 
  sampling method: Non-Probability Sample
  criteria: 
  gender: All
  minimum age: 16 Years
  maximum age: 65 Years
  healthy volunteers: No
  last name: Yu-Chen Fan, MD,PhD
  role: Study Chair
  affiliation: Qilu Hospital of Shandong University
  last name: Yu-Chen Fan, MD,PhD
  phone: 18560082065
  email: fanyuchen@sdu.edu.cn
  citation: Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015 Oct 17;386(10003):1546-55. doi: 10.1016/S0140-6736(15)61412-X. Epub 2015 Jul 28.
  PMID: 26231459
  citation: Wang G, Duan Z. Guidelines for Prevention and Treatment of Chronic Hepatitis B. J Clin Transl Hepatol. 2021 Oct 28;9(5):769-791. doi: 10.14218/JCTH.2021.00209. Epub 2021 Sep 28.
  PMID: 34722192
  citation: Huang DQ, Lim SG. Hepatitis B: Who to treat? A critical review of international guidelines. Liver Int. 2020 Feb;40 Suppl 1:5-14. doi: 10.1111/liv.14365.
  PMID: 32077616
  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
  responsible party type: Sponsor
  mesh term: Hepatitis A
  mesh term: Hepatitis B
  mesh term: Hepatitis B, Chronic
  mesh term: Hepatitis
  mesh term: Hepatitis, Chronic
  sharing ipd: No