<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/NCT01711164</url>
  </required_header>
  <id_info>
    <org_study_id>12-5129-BE</org_study_id>
    <nct_id>NCT01711164</nct_id>
  </id_info>
  <brief_title>The Role of FGL2-FcgammaRIIB Inhibitory Pathway in Human Viral Hepatitis</brief_title>
  <official_title>The Role of FGL2-FcgammaRIIB Inhibitory Pathway in Human Viral Hepatitis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Health Network, Toronto</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Health Network, Toronto</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Viral hepatitis is a serious world health problem affecting over 1 billion people worldwide.&#xD;
      Presently the lack of highly effective treatments results in many patients requiring liver&#xD;
      transplantation or death. The investigators have defined the role of a unique molecule FGL2&#xD;
      and its receptor fc-gammaR and its role in the pathogenesis of both experimental and human&#xD;
      hepatitis. The studies proposed in the present proposal will test the hypothesis that&#xD;
      measuring levels of fgl2 in plasma will identify individuals that will go on to develop&#xD;
      chronic disease and inhibition of binding of fgl2 to its receptor will allow the host with&#xD;
      both acute and chronic disease to develop an appropriate immune response and clear the virus.&#xD;
      The studies will provide rationale for generation of new therapies to improve the treatment&#xD;
      of patients with acute and chronic viral hepatitis by targeting fgl2.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Hepatitis C Virus (HCV) infection affects more than 200 million individuals worldwide. Only a&#xD;
      fraction of infected individuals clear the virus, whereas the majority (70%) develops chronic&#xD;
      infection. The current standard of care, pegylated interferon/ ribavirin (pegIFN/rib) is&#xD;
      effective in only 50% of patients. Patients who fail anti-viral therapy gradually progress to&#xD;
      end-stage liver disease and hepatocellular cancer; which can only be cured by a liver&#xD;
      transplant. The reasons for treatment failure are unclear but involve both viral and host&#xD;
      factors. One significant factor may be impaired T cell function. Chronic HCV infection is&#xD;
      associated with functionally impaired or exhausted cytotoxic T lymphocytes (CTLs), with&#xD;
      decreased anti-viral cytokine production, cytotoxicity and proliferative capacity. The&#xD;
      investigators recently showed that many patients who fail treatment have elevated frequencies&#xD;
      of CD4+CD25+Foxp3+regulatory T cells (Tregs) producing the novel fibrinogen-like-protein 2&#xD;
      (FGL2/fibroleukin) which appears to impair HCV specific immune responses. Binding of FGL2 to&#xD;
      the FcγRIIB receptor leads to inhibition of dendritic cell (DC) maturation, B cell apoptosis&#xD;
      and inhibition of development of effective CD4+and CD8+T and B cell anti-viral responses. In&#xD;
      HCV, increased levels of secreted FGL2 may suppress anti-viral immune responses and promote&#xD;
      disease progression.&#xD;
&#xD;
      Hypothesis: HCV suppresses innate and adaptive anti-viral immune responses through the&#xD;
      FGL2-FcγRIIB inhibitory pathway. Inhibition of this pathway will restore effective&#xD;
      virus-specific immunity and lead to successful viral eradication.&#xD;
&#xD;
      Significance: These studies will establish the importance of FGL2-FcγRIIB inhibitory pathway&#xD;
      in the pathogenesis of HCV chronic infection and provide a novel therapeutic approach to&#xD;
      improve virus eradication and long term patient outcomes.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2014</start_date>
  <completion_date type="Actual">September 2016</completion_date>
  <primary_completion_date type="Actual">May 2016</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>To correlate plasma levels of FGL2 in patients who undergo antiviral therapy for chronic HCV infection with clinical outcome</measure>
    <time_frame>6 months after end of antiviral treatment</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>to correlate levels of FGL2 to numbers and immune function of CD4+ and CD8+ T cells, and DC activity</measure>
    <time_frame>at all timepoints; pre-treatment, at wks 4, 12 and 48 of treatment and 6 months after end of treatment</time_frame>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">106</enrollment>
  <condition>Chronic Hepatitis C Infection</condition>
  <arm_group>
    <arm_group_label>patients</arm_group_label>
    <description>Chronic HCV patients who undergo antiviral therapy</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy controls</arm_group_label>
    <description>healthy controls who are willing to give blood and liver tissue samples</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Patients being followed by hepatologists and considering treatment of Hepatitis C vs&#xD;
        controls derived from potential live liver donors (for transplant)&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Able and willing to give written informed consent&#xD;
&#xD;
          2. Willing to follow the study protocol&#xD;
&#xD;
          3. Between &gt;18 and &lt;70 years of age, both gender&#xD;
&#xD;
          4. No history of active alcohol or drug abuse&#xD;
&#xD;
          5. Adequate contraception for both gender&#xD;
&#xD;
          6. Diagnosis of chronic HCV infection based on two positive serology tests.&#xD;
&#xD;
          7. Pre- and post treatment viral load data must be available&#xD;
&#xD;
          8. Naïve to antiviral treatment&#xD;
&#xD;
          9. A pre treatment liver biopsy should be available for all patients&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. All other genotypes than genotype 1&#xD;
&#xD;
          2. Less than 18 or greater than 70 years of age&#xD;
&#xD;
          3. Pregnancy&#xD;
&#xD;
          4. Co-infection with HBV (hepatitis B virus), HDV (Hepatitis Delta virus) or HIV&#xD;
             co-infection&#xD;
&#xD;
          5. Coexistence of liver disease of other etiology (autoimmune, alcohol)&#xD;
&#xD;
          6. Evidence of hepatocellular carcinoma&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Nazia Selzner, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Health Network, Toronto</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Health Network</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M4G 2C4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <results_reference>
    <citation>Foerster K, Helmy A, Zhu Y, Khattar R, Adeyi OA, Wong KM, Shalev I, Clark DA, Wong PY, Heathcote EJ, Phillips MJ, Grant DR, Renner EL, Levy GA, Selzner N. The novel immunoregulatory molecule FGL2: a potential biomarker for severity of chronic hepatitis C virus infection. J Hepatol. 2010 Oct;53(4):608-15. doi: 10.1016/j.jhep.2010.04.020. Epub 2010 Jun 17.</citation>
    <PMID>20615566</PMID>
  </results_reference>
  <verification_date>November 2016</verification_date>
  <study_first_submitted>October 12, 2012</study_first_submitted>
  <study_first_submitted_qc>October 17, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 22, 2012</study_first_posted>
  <last_update_submitted>November 28, 2016</last_update_submitted>
  <last_update_submitted_qc>November 28, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">November 29, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>HCV</keyword>
  <keyword>T regulatory cells (Tregs)</keyword>
  <keyword>FGL2</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatitis A</mesh_term>
    <mesh_term>Hepatitis C</mesh_term>
    <mesh_term>Hepatitis C, Chronic</mesh_term>
    <mesh_term>Hepatitis, Viral, Human</mesh_term>
    <mesh_term>Hepatitis</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01711164
org study id: 12-5129-BE
nct id: NCT01711164
lead sponsor: 
has dmc: Yes
Viral hepatitis is a serious world health problem affecting over 1 billion people worldwide.
      Presently the lack of highly effective treatments results in many patients requiring liver
      transplantation or death. The investigators have defined the role of a unique molecule FGL2
      and its receptor fc-gammaR and its role in the pathogenesis of both experimental and human
      hepatitis. The studies proposed in the present proposal will test the hypothesis that
      measuring levels of fgl2 in plasma will identify individuals that will go on to develop
      chronic disease and inhibition of binding of fgl2 to its receptor will allow the host with
      both acute and chronic disease to develop an appropriate immune response and clear the virus.
      The studies will provide rationale for generation of new therapies to improve the treatment
      of patients with acute and chronic viral hepatitis by targeting fgl2.
Hepatitis C Virus (HCV) infection affects more than 200 million individuals worldwide. Only a
      fraction of infected individuals clear the virus, whereas the majority (70%) develops chronic
      infection. The current standard of care, pegylated interferon/ ribavirin (pegIFN/rib) is
      effective in only 50% of patients. Patients who fail anti-viral therapy gradually progress to
      end-stage liver disease and hepatocellular cancer; which can only be cured by a liver
      transplant. The reasons for treatment failure are unclear but involve both viral and host
      factors. One significant factor may be impaired T cell function. Chronic HCV infection is
      associated with functionally impaired or exhausted cytotoxic T lymphocytes (CTLs), with
      decreased anti-viral cytokine production, cytotoxicity and proliferative capacity. The
      investigators recently showed that many patients who fail treatment have elevated frequencies
      of CD4+CD25+Foxp3+regulatory T cells (Tregs) producing the novel fibrinogen-like-protein 2
      (FGL2/fibroleukin) which appears to impair HCV specific immune responses. Binding of FGL2 to
      the FcγRIIB receptor leads to inhibition of dendritic cell (DC) maturation, B cell apoptosis
      and inhibition of development of effective CD4+and CD8+T and B cell anti-viral responses. In
      HCV, increased levels of secreted FGL2 may suppress anti-viral immune responses and promote
      disease progression.

      Hypothesis: HCV suppresses innate and adaptive anti-viral immune responses through the
      FGL2-FcγRIIB inhibitory pathway. Inhibition of this pathway will restore effective
      virus-specific immunity and lead to successful viral eradication.

      Significance: These studies will establish the importance of FGL2-FcγRIIB inhibitory pathway
      in the pathogenesis of HCV chronic infection and provide a novel therapeutic approach to
      improve virus eradication and long term patient outcomes.
observational model: Case-Control
time perspective: Prospective
measure: To correlate plasma levels of FGL2 in patients who undergo antiviral therapy for chronic HCV infection with clinical outcome
time frame: 6 months after end of antiviral treatment
measure: to correlate levels of FGL2 to numbers and immune function of CD4+ and CD8+ T cells, and DC activity
time frame: at all timepoints; pre-treatment, at wks 4, 12 and 48 of treatment and 6 months after end of treatment
arm group label: patients
description: Chronic HCV patients who undergo antiviral therapy
arm group label: Healthy controls
description: healthy controls who are willing to give blood and liver tissue samples
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Nazia Selzner, MD PhD
role: Principal Investigator
affiliation: University Health Network, Toronto
facility: 
country: Canada
citation: Foerster K, Helmy A, Zhu Y, Khattar R, Adeyi OA, Wong KM, Shalev I, Clark DA, Wong PY, Heathcote EJ, Phillips MJ, Grant DR, Renner EL, Levy GA, Selzner N. The novel immunoregulatory molecule FGL2: a potential biomarker for severity of chronic hepatitis C virus infection. J Hepatol. 2010 Oct;53(4):608-15. doi: 10.1016/j.jhep.2010.04.020. Epub 2010 Jun 17.
PMID: 20615566
responsible party type: Sponsor
mesh term: Hepatitis A
mesh term: Hepatitis C
mesh term: Hepatitis C, Chronic
mesh term: Hepatitis, Viral, Human
mesh term: Hepatitis