<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/NCT02985450</url>
  </required_header>
  <id_info>
    <org_study_id>REB16-0274</org_study_id>
    <nct_id>NCT02985450</nct_id>
  </id_info>
  <brief_title>A Prospective Study of HBV Immunity and HBV Vaccination in Patients With NAFLD in Canada</brief_title>
  <official_title>A Prospective Study of Hepatitis B Virus (HBV) Immunity and Hepatitis B Vaccination in Patients With Non Alcoholic Fatty Liver Disease (NAFLD) in Canada</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Calgary</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Canadian Institutes of Health Research (CIHR)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>GlaxoSmithKline</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Calgary</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      (1) Due to missed childhood vaccination programs, the majority of adult patients with NAFLD&#xD;
      in Canada do not have immunity to hepatitis B. (2) Adults with NAFLD who receive the HBV&#xD;
      vaccine have reduced immunogenic responses in the setting of obesity (i.e., protective&#xD;
      anti-HBs titres). Aims: (1) To determine the sero-prevalence of immunity against hepatitis B&#xD;
      in a cohort of prospectively evaluated adult NAFLD patients. (2) To prospectively determine&#xD;
      HBV vaccine responses (anti-HBs titres) in adult NAFLD patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The hepatitis B virus (HBV) is truly a global human pathogen that affects at least 2 billion&#xD;
      people worldwide including ~240 million chronic hepatitis B (CHB) carriers that are at risk&#xD;
      for end-stage liver disease. The diagnosis of CHB is confirmed by the persistence of the HBV&#xD;
      surface antigen (HBsAg) in serum for &gt;6 months. However, a latent form of HBV infection known&#xD;
      as occult hepatitis B infection (OBI) characterized by low-level viremia (i.e., HBV DNA &lt; 200&#xD;
      IU/ml) despite undetectable serum HBsAg has been described with unclear clinical&#xD;
      consequences.&#xD;
&#xD;
      A safe and effective HBV vaccine has been available for ~3 decades and consists of&#xD;
      recombinant HBsAg which contains the major viral antigenic epitopes and induces a protective&#xD;
      neutralizing antibody to HBsAg (anti-HBs) response in &gt;85% of children vaccinated. Canada is&#xD;
      a low HBV-endemic region and in Alberta, and Ontario, public health uses maternal screening&#xD;
      for HBsAg to identify babies at-risk for CHB. Thus, all infants born to HBsAg (+) mothers are&#xD;
      given passive-active immunoprophylaxis with hepatitis B immune globulin (HBIG) and the HBV&#xD;
      vaccine within 12 hours of birth, as well as 2 doses at ~2 and ~6 months of age. Testing of&#xD;
      the infants for anti-HBs is recommended at 9 months to ensure immunity. In the late 1990's, a&#xD;
      universal HBV childhood vaccination program was initiated in all Canadian provinces and&#xD;
      jurisdictions. In Alberta and in Ontario, school-age children are scheduled to receive the&#xD;
      3-dose HBV vaccine series in grade 5. However there remain a significant proportion of adult&#xD;
      Canadians (i.e., born before 1985) who missed childhood vaccination programs. Although&#xD;
      current guidelines recommend that certain high-risk populations receive hepatitis B&#xD;
      immunization, appropriate identification and compliance is generally much lower in adults&#xD;
      compared to children.&#xD;
&#xD;
      According to the most recent Canadian Association for the Study of Liver Disease guidelines,&#xD;
      all adults with diabetes, as well as all patients with chronic liver disease should receive&#xD;
      the hepatitis B vaccine. The basis for these recommendations are two-fold, (1) diabetics may&#xD;
      be at risk of blood-borne virus (BBV) exposure through contact with contaminated blood&#xD;
      glucose monitoring devices and (2) diabetic patients are at increased risk of the metabolic&#xD;
      syndrome and the development of non-alcoholic fatty liver disease (NAFLD). The improvement in&#xD;
      blood glucose monitoring devices, and increased knowledge has reduced the risk of HBV&#xD;
      exposure in patients with diabetes. Further, the investigators' initial seroepidemiological&#xD;
      survey of acute HBV outbreaks in Alberta revealed a decreasing prevalence in diabetic&#xD;
      patients. Therefore the main incentive for HBV vaccination in diabetics is due to the&#xD;
      concomitant risk of the metabolic syndrome and advanced liver disease due to NAFLD. There is&#xD;
      limited data on HBV vaccination in NAFLD patients. Further studies are required in a North&#xD;
      American adult (Canadian population).&#xD;
&#xD;
      The investigators propose that adults with NAFLD should undergo comprehensive screening for&#xD;
      hepatitis B immunogenicity, in addition to screening for infection, and catch up or booster&#xD;
      vaccinations should be administered to non-immunized patients with confirmatory immunity&#xD;
      testing thereafter.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 2016</start_date>
  <completion_date type="Actual">January 2021</completion_date>
  <primary_completion_date type="Actual">January 2021</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Anti-HBs Titres (IU/L)</measure>
    <time_frame>1 month after completion of the vaccine series</time_frame>
    <description>to determine how NAFLD-associated metabolic risk factors and liver inflammation / fibrosis affects vaccine response</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of Memory T Cells and HBsAg-specific-proliferation of CD3 + CD4+ TH Cells</measure>
    <time_frame>1 month after completion of the vaccine series</time_frame>
    <description>to determine how NAFLD-associated metabolic risk factors and liver inflammation / fibrosis affects vaccine response. Fresh (or cryopreserved in 4 patients) PBMC (~106) were labeled with 1 μM carboxyfluorescein-diacetate-succinimidyl-ester. Labeled PBMC were stimulated with 5 μg HBsAg) in RPMI 1640 with 10% FBS and 2mmol/L glutamine. Anti-CD3 (1 μg/mL) and anti-CD28 (5 μg/mL) stimulated cells served as a positive control.&#xD;
Unstimulated DMSO-treated cells were used as negative controls. Cells were cultured in triplicates and plates incubated at 37 °C with 5% CO2 for ~8 days. Cell proliferation was assessed on day 8. SI was calculated as % CFSE low cells in stimulated cells / % CFSE low cells in the unstimulated control46. SI&gt; 3 was considered positive for HBsAg-specific proliferation. Cells were stained using the memory T-cell panel and analyzed by flow-cytometry</description>
  </primary_outcome>
  <enrollment type="Actual">82</enrollment>
  <condition>Non-Alcoholic Fatty Liver Disease</condition>
  <condition>Hepatitis B</condition>
  <condition>Vaccine Reaction</condition>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Engerix-B</intervention_name>
    <description>Hepatitis B Vaccine</description>
    <other_name>Twinrix</other_name>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      PBMCs will be cryopreserved to assess HBV specific T and B cell responses.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        NAFLD patients will be recruited from large tertiary liver clinics in Canada&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects 18-60 years of age, who provide signed informed consent&#xD;
&#xD;
          -  Diagnosis of NAFLD/NASH according to expert assessment (by imaging, TE, abnormal lab&#xD;
             tests and/or liver biopsy)&#xD;
&#xD;
          -  No evidence of prior infection or immunity to hepatitis B (negative HBsAg, anti-HBs,&#xD;
             anti-HBc).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subjects &lt; 18 years of age,&#xD;
&#xD;
          -  Subjects who refused vaccination&#xD;
&#xD;
          -  Have documented immunity / prior exposure to hepatitis B (i.e., positive for ant-HBs,&#xD;
             anti-HBc, HBsAg)&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  HIV-positive&#xD;
&#xD;
          -  Decompensated cirrhosis (i.e., Child-Pugh Class B or C) due to impact on immune&#xD;
             response.&#xD;
&#xD;
          -  Subjects &gt;60 y will be excluded, due to effect of age and reduced response to HBV&#xD;
             vaccination.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Carla Coffin</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Calgary</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Calgary</name>
      <address>
        <city>Calgary</city>
        <state>Alberta</state>
        <zip>T2N 4Z6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>June 2018</verification_date>
  <study_first_submitted>December 1, 2016</study_first_submitted>
  <study_first_submitted_qc>December 2, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 7, 2016</study_first_posted>
  <results_first_submitted>January 13, 2021</results_first_submitted>
  <results_first_submitted_qc>November 2, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">November 3, 2021</results_first_posted>
  <last_update_submitted>November 2, 2021</last_update_submitted>
  <last_update_submitted_qc>November 2, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">November 3, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatitis A</mesh_term>
    <mesh_term>Hepatitis B</mesh_term>
    <mesh_term>Hepatitis</mesh_term>
    <mesh_term>Liver Diseases</mesh_term>
    <mesh_term>Fatty Liver</mesh_term>
    <mesh_term>Non-alcoholic Fatty Liver Disease</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>June 13, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/50/NCT02985450/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>June 14, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/50/NCT02985450/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Patients with non-alcoholic fatty liver disease (NAFLD), without prior exposure to hepatitis B or hepatitis B vaccine. Recruitment period was August 2016-March 2020.</recruitment_details>
      <pre_assignment_details>No significant events were noted. 7 patients were lost to follow-up.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>HBV Vaccine Cohort</title>
          <description>Of 82 participants, all received the HBV vaccine. Vaccines were not blinded as patients were followed as standard of care. We followed the product monograph for TWINRIX and Engerix vaccines.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="82"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="75"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>7 patients lost to follow-up.</population>
      <group_list>
        <group group_id="B1">
          <title>HBV Vaccine Cohort</title>
          <description>Of 82 participants, all received the HBV vaccine. Vaccines were not blinded as patients were followed as standard of care.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="82"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="82"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="82"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="48.5" spread="8.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="48.5" spread="8.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="40"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="81"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Canada</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="82"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>BMI (body mass index)</title>
          <units>kg/m^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="33.6" spread="6.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Anti-HBs Titres (IU/L)</title>
        <description>to determine how NAFLD-associated metabolic risk factors and liver inflammation / fibrosis affects vaccine response</description>
        <time_frame>1 month after completion of the vaccine series</time_frame>
        <population>Anti-HBs levels were compared between two groups: low and high-risk obesity patients with NAFLD.</population>
        <group_list>
          <group group_id="O1">
            <title>BMI &lt; 35</title>
            <description>40 patients with BMI &lt; 35</description>
          </group>
          <group group_id="O2">
            <title>BMI &gt; 35</title>
            <description>28 patients with BMI &gt; 35</description>
          </group>
        </group_list>
        <measure>
          <title>Anti-HBs Titres (IU/L)</title>
          <description>to determine how NAFLD-associated metabolic risk factors and liver inflammation / fibrosis affects vaccine response</description>
          <population>Anti-HBs levels were compared between two groups: low and high-risk obesity patients with NAFLD.</population>
          <units>Anti-HBS IU/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="40"/>
                <count group_id="O2" value="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="642" spread="68.2"/>
                    <measurement group_id="O2" value="385" spread="79"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.02</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>513.5</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>73.6</dispersion_value>
            <ci_n_sides>2-Sided</ci_n_sides>
            <estimate_desc>Anti-HBs levels difference: high risk obesity group - low risk obesity group NAFLD patients</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Assessment of Memory T Cells and HBsAg-specific-proliferation of CD3 + CD4+ TH Cells</title>
        <description>to determine how NAFLD-associated metabolic risk factors and liver inflammation / fibrosis affects vaccine response. Fresh (or cryopreserved in 4 patients) PBMC (~106) were labeled with 1 μM carboxyfluorescein-diacetate-succinimidyl-ester. Labeled PBMC were stimulated with 5 μg HBsAg) in RPMI 1640 with 10% FBS and 2mmol/L glutamine. Anti-CD3 (1 μg/mL) and anti-CD28 (5 μg/mL) stimulated cells served as a positive control.&#xD;
Unstimulated DMSO-treated cells were used as negative controls. Cells were cultured in triplicates and plates incubated at 37 °C with 5% CO2 for ~8 days. Cell proliferation was assessed on day 8. SI was calculated as % CFSE low cells in stimulated cells / % CFSE low cells in the unstimulated control46. SI&gt; 3 was considered positive for HBsAg-specific proliferation. Cells were stained using the memory T-cell panel and analyzed by flow-cytometry</description>
        <time_frame>1 month after completion of the vaccine series</time_frame>
        <population>17 patients with BMI &lt; 35 and 14 patients with BMI &gt; 35 for PBMC analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>BMI &lt; 35</title>
            <description>17 patients with BMI &lt; 35 and PBMCs collected for analysis.</description>
          </group>
          <group group_id="O2">
            <title>BMI &gt; 35</title>
            <description>14 patients with BMI &gt; 35 and PBMCs collected for analysis.</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of Memory T Cells and HBsAg-specific-proliferation of CD3 + CD4+ TH Cells</title>
          <description>to determine how NAFLD-associated metabolic risk factors and liver inflammation / fibrosis affects vaccine response. Fresh (or cryopreserved in 4 patients) PBMC (~106) were labeled with 1 μM carboxyfluorescein-diacetate-succinimidyl-ester. Labeled PBMC were stimulated with 5 μg HBsAg) in RPMI 1640 with 10% FBS and 2mmol/L glutamine. Anti-CD3 (1 μg/mL) and anti-CD28 (5 μg/mL) stimulated cells served as a positive control.&#xD;
Unstimulated DMSO-treated cells were used as negative controls. Cells were cultured in triplicates and plates incubated at 37 °C with 5% CO2 for ~8 days. Cell proliferation was assessed on day 8. SI was calculated as % CFSE low cells in stimulated cells / % CFSE low cells in the unstimulated control46. SI&gt; 3 was considered positive for HBsAg-specific proliferation. Cells were stained using the memory T-cell panel and analyzed by flow-cytometry</description>
          <population>17 patients with BMI &lt; 35 and 14 patients with BMI &gt; 35 for PBMC analysis.</population>
          <units>Stimulation index</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="14"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.1" spread="0.68"/>
                    <measurement group_id="O2" value="3.1" spread="0.62"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Each patient was assessed with 18 months of their baseline visit. Antibodies titers were assessed within 3 months after their last hepatitis vaccine dose.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>HBV Vaccine Cohort</title>
          <description>Of 82 participants, all received the HBV vaccine. Vaccines were not blinded as patients were followed as standard of care.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="82"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="82"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="82"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr.</name_or_title>
      <organization>Carla Coffin</organization>
      <phone>403-220-7808</phone>
      <email>cscoffin@ucalgary.ca</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02985450
org study id: REB16-0274
nct id: NCT02985450
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
(1) Due to missed childhood vaccination programs, the majority of adult patients with NAFLD
      in Canada do not have immunity to hepatitis B. (2) Adults with NAFLD who receive the HBV
      vaccine have reduced immunogenic responses in the setting of obesity (i.e., protective
      anti-HBs titres). Aims: (1) To determine the sero-prevalence of immunity against hepatitis B
      in a cohort of prospectively evaluated adult NAFLD patients. (2) To prospectively determine
      HBV vaccine responses (anti-HBs titres) in adult NAFLD patients.
The hepatitis B virus (HBV) is truly a global human pathogen that affects at least 2 billion
      people worldwide including ~240 million chronic hepatitis B (CHB) carriers that are at risk
      for end-stage liver disease. The diagnosis of CHB is confirmed by the persistence of the HBV
      surface antigen (HBsAg) in serum for >6 months. However, a latent form of HBV infection known
      as occult hepatitis B infection (OBI) characterized by low-level viremia (i.e., HBV DNA < 200
      IU/ml) despite undetectable serum HBsAg has been described with unclear clinical
      consequences.

      A safe and effective HBV vaccine has been available for ~3 decades and consists of
      recombinant HBsAg which contains the major viral antigenic epitopes and induces a protective
      neutralizing antibody to HBsAg (anti-HBs) response in >85% of children vaccinated. Canada is
      a low HBV-endemic region and in Alberta, and Ontario, public health uses maternal screening
      for HBsAg to identify babies at-risk for CHB. Thus, all infants born to HBsAg (+) mothers are
      given passive-active immunoprophylaxis with hepatitis B immune globulin (HBIG) and the HBV
      vaccine within 12 hours of birth, as well as 2 doses at ~2 and ~6 months of age. Testing of
      the infants for anti-HBs is recommended at 9 months to ensure immunity. In the late 1990's, a
      universal HBV childhood vaccination program was initiated in all Canadian provinces and
      jurisdictions. In Alberta and in Ontario, school-age children are scheduled to receive the
      3-dose HBV vaccine series in grade 5. However there remain a significant proportion of adult
      Canadians (i.e., born before 1985) who missed childhood vaccination programs. Although
      current guidelines recommend that certain high-risk populations receive hepatitis B
      immunization, appropriate identification and compliance is generally much lower in adults
      compared to children.

      According to the most recent Canadian Association for the Study of Liver Disease guidelines,
      all adults with diabetes, as well as all patients with chronic liver disease should receive
      the hepatitis B vaccine. The basis for these recommendations are two-fold, (1) diabetics may
      be at risk of blood-borne virus (BBV) exposure through contact with contaminated blood
      glucose monitoring devices and (2) diabetic patients are at increased risk of the metabolic
      syndrome and the development of non-alcoholic fatty liver disease (NAFLD). The improvement in
      blood glucose monitoring devices, and increased knowledge has reduced the risk of HBV
      exposure in patients with diabetes. Further, the investigators' initial seroepidemiological
      survey of acute HBV outbreaks in Alberta revealed a decreasing prevalence in diabetic
      patients. Therefore the main incentive for HBV vaccination in diabetics is due to the
      concomitant risk of the metabolic syndrome and advanced liver disease due to NAFLD. There is
      limited data on HBV vaccination in NAFLD patients. Further studies are required in a North
      American adult (Canadian population).

      The investigators propose that adults with NAFLD should undergo comprehensive screening for
      hepatitis B immunogenicity, in addition to screening for infection, and catch up or booster
      vaccinations should be administered to non-immunized patients with confirmatory immunity
      testing thereafter.
observational model: Cohort
time perspective: Prospective
measure: Anti-HBs Titres (IU/L)
time frame: 1 month after completion of the vaccine series
description: to determine how NAFLD-associated metabolic risk factors and liver inflammation / fibrosis affects vaccine response
measure: Assessment of Memory T Cells and HBsAg-specific-proliferation of CD3 + CD4+ TH Cells
time frame: 1 month after completion of the vaccine series
description: to determine how NAFLD-associated metabolic risk factors and liver inflammation / fibrosis affects vaccine response. Fresh (or cryopreserved in 4 patients) PBMC (~106) were labeled with 1 μM carboxyfluorescein-diacetate-succinimidyl-ester. Labeled PBMC were stimulated with 5 μg HBsAg) in RPMI 1640 with 10% FBS and 2mmol/L glutamine. Anti-CD3 (1 μg/mL) and anti-CD28 (5 μg/mL) stimulated cells served as a positive control.
Unstimulated DMSO-treated cells were used as negative controls. Cells were cultured in triplicates and plates incubated at 37 °C with 5% CO2 for ~8 days. Cell proliferation was assessed on day 8. SI was calculated as % CFSE low cells in stimulated cells / % CFSE low cells in the unstimulated control46. SI> 3 was considered positive for HBsAg-specific proliferation. Cells were stained using the memory T-cell panel and analyzed by flow-cytometry
intervention type: Biological
intervention name: Engerix-B
description: Hepatitis B Vaccine
other name: Twinrix
PBMCs will be cryopreserved to assess HBV specific T and B cell responses.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: Carla Coffin
role: Principal Investigator
affiliation: University of Calgary
facility: 
country: Canada
responsible party type: Sponsor
mesh term: Hepatitis A
mesh term: Hepatitis B
mesh term: Hepatitis
mesh term: Liver Diseases
mesh term: Fatty Liver
mesh term: Non-alcoholic Fatty Liver Disease
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 