<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/NCT03038802</url>
  </required_header>
  <id_info>
    <org_study_id>HBV003</org_study_id>
    <nct_id>NCT03038802</nct_id>
  </id_info>
  <brief_title>A Randomised Controlled Phase 1 Study of Vaccine Therapy for Control or Cure of Chronic Hepatitis B Virus Infection</brief_title>
  <acronym>HBV003</acronym>
  <official_title>A Randomised Controlled Phase 1 Study of Vaccine Therapy for Control or Cure of Chronic Hepatitis B Virus Infection</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vaxine Pty Ltd</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Australian Respiratory and Sleep Medicine Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Vaxine Pty Ltd</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>
      This is a pilot study to determine the safety and efficacy of a novel adjuvanted hepatitis B&#xD;
      virus (HBV) vaccine formulated as a potential therapeutic vaccine against chronic HBV&#xD;
      infection. An ongoing human clinical trial of this HBV vaccine in a prophylactic setting has&#xD;
      confirmed this vaccine to be more effective at inducing seroconversion as measured by&#xD;
      development of Hepatitis B surface antibody (HBsAb) in poor responder subjects than the&#xD;
      standard alum-adjuvanted HBV vaccine, providing promise that this new vaccine may also be&#xD;
      able to induce HBV viral control and/or seroconversion in chronically infected subjects&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Prophylactic immunisation with HBsAg-based vaccines leads to development of HBsAg antibodies&#xD;
      that provide protection against HBV infection. Modern HBV vaccines are based on recombinant&#xD;
      HBsAg produced by expression in yeast expression systems. For infants whose mothers are HBsAg&#xD;
      positive, the first HBV vaccine dose is given at birth and three further doses are&#xD;
      administrated during the following 12 months at 2, 4 and 6 or 12 months. Studies have shown&#xD;
      that these HBV vaccines are 90 to 95% effective in preventing children from developing&#xD;
      chronic infection if they have not yet been infected. Since 1982 over one billion doses of&#xD;
      HBV vaccine have been used worldwide. However a number of groups have poor responses to the&#xD;
      existing HBV vaccines and these include older adults (age &gt; 40) and patients with&#xD;
      immunodeficiency, diabetes or renal impairment. A pilot clinical study demonstrated that&#xD;
      standard anti-HBV vaccination could reduce HBV replication in 50% of chronic carriers. A&#xD;
      multicentre trial, showed both the efficacy and the limitations of this approach. This study&#xD;
      included 118 treatment-naive patients, with detectable serum HBV DNA using a standard liquid&#xD;
      hybridization study and biopsy-proven chronic hepatitis pre-vaccination. Over a 12-month&#xD;
      period, they were given either five intradermal injections of 20 µg of a pre S2:S HBV vaccine&#xD;
      (GenHevac B.Pasteur-Merieux) or a standard HBV vaccine (Recombivax, MSD) or no treatment.&#xD;
      Three months after the first three vaccine injections, the percentage of serum HBV DNA&#xD;
      negativity was higher in the vaccine groups (15.5%) than in the control group (2.7%). After 1&#xD;
      year follow-up and five vaccine injections, there was no difference in the rate of serum HBV&#xD;
      DNA negativity, but those receiving HBV vaccines had significantly decreased HBV viral load&#xD;
      between 6 and 12 months when compared to the control group. The rate of HBe:anti-HBe&#xD;
      seroconversion did not differ between the vaccinated and unvaccinated groups, but early HBeAg&#xD;
      negativity and anti-HBe detection after 6 months of follow-up was seen only in vaccinated&#xD;
      patients (8 and 15% in groups B (Recombivax.) and C (GenHevac B.), respectively, compared&#xD;
      with 0% in the controls). Analysis of the vaccine-induced immune responses in 40 patients&#xD;
      with HBV chronic hepatitis during this vaccine trial showed that vaccination elicited T cell&#xD;
      proliferative responses in 7 of 27 patients who received the vaccine versus none of the&#xD;
      unvaccinated control group. These specific responses for envelope antigen were mediated by&#xD;
      CD4 T cells that produced high levels of gamma interferon. The reduction of serum HBV-DNA in&#xD;
      some of these patients suggests that induction of CD4 T cell responses could be important in&#xD;
      controlling viremia after vaccine therapy of HBV chronic carriers.&#xD;
&#xD;
      Experiments in transgenic mice that constitutively express HBV in the liver as a model of&#xD;
      asymptomatic chronic HBV carriers have shown that immunization can overcome functional&#xD;
      tolerance to HBV by inducing a specific antiviral immune response. The study vaccine was&#xD;
      tested for its ability to induce seroconversion in a HBV transgenic mouse model. The results&#xD;
      confirmed that the vaccine induced a high titre of anti-HBsAg antibodies and suppressed HBV&#xD;
      virus load in the liver. Importantly from a safety perspective no evidence of a flare in&#xD;
      liver disease as reflected by elevation of liver functions tests, was seen despite evidence&#xD;
      the vaccine suppressed liver virus. The vaccinated mice had the lowest levels of liver&#xD;
      transaminases, consistent with the vaccine reducing virus-mediated damage to the liver.&#xD;
&#xD;
      This study will test the hypothesis that the investigational vaccine will boost HBV antibody&#xD;
      and T cell responses in chronically infected patients and thereby improve HBV viral control&#xD;
      and opportunity for seroconversion. As this is an exploratory study, subjects with chronic&#xD;
      HBV infection will be enrolled whether or not they are on current antiviral treatment. This&#xD;
      will then allow comparison of vaccine effects in subjects on and off concomitant antiviral&#xD;
      treatment, with this data used to assist the design of future studies. The study will test&#xD;
      the hypothesis that a potent preS HBV vaccine including Advax adjuvant will enhance both&#xD;
      humoral and cellular immunity thereby helping to control chronic hepatitis B infection. The&#xD;
      ultimate goal is to induce HBsAg seroconversion and effect permanent clearance of HBV or at a&#xD;
      minimum to enable better immune control of viral replication. This pilot study will collect&#xD;
      preliminary data on the safety and efficacy of this vaccine approach in chronically HBV&#xD;
      infected individuals, as a precursor to larger efficacy studies in the future.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">September 2023</start_date>
  <completion_date type="Anticipated">December 2025</completion_date>
  <primary_completion_date type="Anticipated">December 2025</primary_completion_date>
  <phase>Phase 1/Phase 2</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>Triple (Participant, Investigator, Outcomes Assessor)</masking>
    <masking_description>Participants, the investigator and outcomes assessors will be blinded as to which vaccine the subject has received</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Safety assessment: Frequency of vaccine-related adverse events relative to active comparator vaccine</measure>
    <time_frame>12 months post immunisation</time_frame>
    <description>Frequency of vaccine-related adverse events relative to active comparator vaccine</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Viral load</measure>
    <time_frame>1 and 12 months post final immunisation</time_frame>
    <description>Suppression of HBV viral load</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Seroconversion</measure>
    <time_frame>1 and 12 months post final immunisation</time_frame>
    <description>Seroconversion to e antigen (if anti HBe negative at baseline) and seroconversion to surface antigen</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>T-cell response</measure>
    <time_frame>1 and 12 months post final immunisation</time_frame>
    <description>Development of memory T-cell responses to HBV</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>B cell response</measure>
    <time_frame>1 and 12 months post final immunisation</time_frame>
    <description>Development of memory B-cell responses to HBV</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Chronic Hepatitis b</condition>
  <arm_group>
    <arm_group_label>Standard vaccine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Subjects will receive regular intramuscular injections of a commercial hepatitis B vaccine (HBsAg containing aluminium hydroxide adjuvant) according to the same study schedule as the subjects in the experimental arm</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Experimental therapeutic vaccine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive regular intramuscular injections of the experimental therapeutic hepatitis B vaccine (preS HBsAg containing Advax-2 adjuvant) in two cycles with the first cycle of four immunisations administered on days 0, 14, 28, 42. and the second cycle of four immunisations on days 70, 84, 98, and 112.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Therapeutic hepatitis B vaccine</intervention_name>
    <description>HBV vaccine based on unique combination of recombinant PreS hepatitis B surface antigen particles formulated with Advax-2 adjuvant</description>
    <arm_group_label>Experimental therapeutic vaccine</arm_group_label>
    <other_name>Hepadvax(TM)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Commercial Hepatitis B vaccine</intervention_name>
    <description>Commercially available prophylactic hepatitis B vaccine formulated with alum adjuvant</description>
    <arm_group_label>Standard vaccine</arm_group_label>
    <other_name>Engerix B</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female&#xD;
&#xD;
          -  18 years of age or older&#xD;
&#xD;
          -  Current evidence of HBV chronic infection (with or without cirrhosis) as indicated by&#xD;
             detection of HBsAg and/or Hepatitis B DNA (Subjects on current nucleoside therapy may&#xD;
             have no detectable Hep B DNA)&#xD;
&#xD;
          -  If child bearing age, using contraception (barrier method, IUD or oral contraception)&#xD;
&#xD;
          -  Able to provide written informed consent&#xD;
&#xD;
          -  Willing and able to comply with the protocol for the duration of the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Positive for antibody to hepatitis B core antigen (anti-HBc) IgM with negative results&#xD;
             for the rest of the HBV markers, indicating acute infection,&#xD;
&#xD;
          -  Positive for anti-delta virus, or anti-hepatitis C virus or HIV&#xD;
&#xD;
          -  Childs Pugh Score for Cirrhosis Mortality of Child grade B or greater&#xD;
&#xD;
          -  Liver transaminases greater than 5 times the upper limit of normal&#xD;
&#xD;
          -  History of severe allergic reaction to hepatitis B vaccine.&#xD;
&#xD;
          -  Pregnancy or female of child-bearing age not using effective method of contraception.&#xD;
&#xD;
          -  Presence of any other organ-specific disease that in the opinion of the investigator&#xD;
             may result in risk to the subject from involvement in the study&#xD;
&#xD;
          -  Current alcohol or drug abuse that in the opinion of the investigator may result in&#xD;
             non-compliance.&#xD;
&#xD;
          -  Participation in another clinical trial with an investigational agent within 30 days&#xD;
             preceding initiation of treatment&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Nikolai Petrovsky, MBBS/PhD</last_name>
    <role>Study Director</role>
    <affiliation>Vaxine Pty Ltd</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Sharen Pringle, RN</last_name>
    <phone>0437033400</phone>
    <email>admin@arasmi.org</email>
  </overall_contact>
  <location>
    <facility>
      <name>ARASMI</name>
      <address>
        <city>Adelaide</city>
        <state>South Australia</state>
        <zip>5046</zip>
        <country>Australia</country>
      </address>
    </facility>
    <contact>
      <last_name>Dimitar Sajkov, MBBS, PhD</last_name>
    </contact>
    <investigator>
      <last_name>Dimitar Sajkov, MBBS, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Australia</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>January 30, 2017</study_first_submitted>
  <study_first_submitted_qc>January 31, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">February 1, 2017</study_first_posted>
  <last_update_submitted>March 28, 2023</last_update_submitted>
  <last_update_submitted_qc>March 28, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 31, 2023</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 B, Chronic</mesh_term>
    <mesh_term>Virus Diseases</mesh_term>
    <mesh_term>Herpesviridae Infections</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>Vaccines</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03038802
org study id: HBV003
nct id: NCT03038802
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is a pilot study to determine the safety and efficacy of a novel adjuvanted hepatitis B
      virus (HBV) vaccine formulated as a potential therapeutic vaccine against chronic HBV
      infection. An ongoing human clinical trial of this HBV vaccine in a prophylactic setting has
      confirmed this vaccine to be more effective at inducing seroconversion as measured by
      development of Hepatitis B surface antibody (HBsAb) in poor responder subjects than the
      standard alum-adjuvanted HBV vaccine, providing promise that this new vaccine may also be
      able to induce HBV viral control and/or seroconversion in chronically infected subjects
Prophylactic immunisation with HBsAg-based vaccines leads to development of HBsAg antibodies
      that provide protection against HBV infection. Modern HBV vaccines are based on recombinant
      HBsAg produced by expression in yeast expression systems. For infants whose mothers are HBsAg
      positive, the first HBV vaccine dose is given at birth and three further doses are
      administrated during the following 12 months at 2, 4 and 6 or 12 months. Studies have shown
      that these HBV vaccines are 90 to 95% effective in preventing children from developing
      chronic infection if they have not yet been infected. Since 1982 over one billion doses of
      HBV vaccine have been used worldwide. However a number of groups have poor responses to the
      existing HBV vaccines and these include older adults (age > 40) and patients with
      immunodeficiency, diabetes or renal impairment. A pilot clinical study demonstrated that
      standard anti-HBV vaccination could reduce HBV replication in 50% of chronic carriers. A
      multicentre trial, showed both the efficacy and the limitations of this approach. This study
      included 118 treatment-naive patients, with detectable serum HBV DNA using a standard liquid
      hybridization study and biopsy-proven chronic hepatitis pre-vaccination. Over a 12-month
      period, they were given either five intradermal injections of 20 µg of a pre S2:S HBV vaccine
      (GenHevac B.Pasteur-Merieux) or a standard HBV vaccine (Recombivax, MSD) or no treatment.
      Three months after the first three vaccine injections, the percentage of serum HBV DNA
      negativity was higher in the vaccine groups (15.5%) than in the control group (2.7%). After 1
      year follow-up and five vaccine injections, there was no difference in the rate of serum HBV
      DNA negativity, but those receiving HBV vaccines had significantly decreased HBV viral load
      between 6 and 12 months when compared to the control group. The rate of HBe:anti-HBe
      seroconversion did not differ between the vaccinated and unvaccinated groups, but early HBeAg
      negativity and anti-HBe detection after 6 months of follow-up was seen only in vaccinated
      patients (8 and 15% in groups B (Recombivax.) and C (GenHevac B.), respectively, compared
      with 0% in the controls). Analysis of the vaccine-induced immune responses in 40 patients
      with HBV chronic hepatitis during this vaccine trial showed that vaccination elicited T cell
      proliferative responses in 7 of 27 patients who received the vaccine versus none of the
      unvaccinated control group. These specific responses for envelope antigen were mediated by
      CD4 T cells that produced high levels of gamma interferon. The reduction of serum HBV-DNA in
      some of these patients suggests that induction of CD4 T cell responses could be important in
      controlling viremia after vaccine therapy of HBV chronic carriers.

      Experiments in transgenic mice that constitutively express HBV in the liver as a model of
      asymptomatic chronic HBV carriers have shown that immunization can overcome functional
      tolerance to HBV by inducing a specific antiviral immune response. The study vaccine was
      tested for its ability to induce seroconversion in a HBV transgenic mouse model. The results
      confirmed that the vaccine induced a high titre of anti-HBsAg antibodies and suppressed HBV
      virus load in the liver. Importantly from a safety perspective no evidence of a flare in
      liver disease as reflected by elevation of liver functions tests, was seen despite evidence
      the vaccine suppressed liver virus. The vaccinated mice had the lowest levels of liver
      transaminases, consistent with the vaccine reducing virus-mediated damage to the liver.

      This study will test the hypothesis that the investigational vaccine will boost HBV antibody
      and T cell responses in chronically infected patients and thereby improve HBV viral control
      and opportunity for seroconversion. As this is an exploratory study, subjects with chronic
      HBV infection will be enrolled whether or not they are on current antiviral treatment. This
      will then allow comparison of vaccine effects in subjects on and off concomitant antiviral
      treatment, with this data used to assist the design of future studies. The study will test
      the hypothesis that a potent preS HBV vaccine including Advax adjuvant will enhance both
      humoral and cellular immunity thereby helping to control chronic hepatitis B infection. The
      ultimate goal is to induce HBsAg seroconversion and effect permanent clearance of HBV or at a
      minimum to enable better immune control of viral replication. This pilot study will collect
      preliminary data on the safety and efficacy of this vaccine approach in chronically HBV
      infected individuals, as a precursor to larger efficacy studies in the future.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
masking description: Participants, the investigator and outcomes assessors will be blinded as to which vaccine the subject has received
measure: Safety assessment: Frequency of vaccine-related adverse events relative to active comparator vaccine
time frame: 12 months post immunisation
description: Frequency of vaccine-related adverse events relative to active comparator vaccine
measure: Viral load
time frame: 1 and 12 months post final immunisation
description: Suppression of HBV viral load
measure: Seroconversion
time frame: 1 and 12 months post final immunisation
description: Seroconversion to e antigen (if anti HBe negative at baseline) and seroconversion to surface antigen
measure: T-cell response
time frame: 1 and 12 months post final immunisation
description: Development of memory T-cell responses to HBV
measure: B cell response
time frame: 1 and 12 months post final immunisation
description: Development of memory B-cell responses to HBV
arm group label: Standard vaccine
arm group type: Active Comparator
description: Subjects will receive regular intramuscular injections of a commercial hepatitis B vaccine (HBsAg containing aluminium hydroxide adjuvant) according to the same study schedule as the subjects in the experimental arm
arm group label: Experimental therapeutic vaccine
arm group type: Experimental
description: Subjects will receive regular intramuscular injections of the experimental therapeutic hepatitis B vaccine (preS HBsAg containing Advax-2 adjuvant) in two cycles with the first cycle of four immunisations administered on days 0, 14, 28, 42. and the second cycle of four immunisations on days 70, 84, 98, and 112.
intervention type: Biological
intervention name: Therapeutic hepatitis B vaccine
description: HBV vaccine based on unique combination of recombinant PreS hepatitis B surface antigen particles formulated with Advax-2 adjuvant
arm group label: Experimental therapeutic vaccine
other name: Hepadvax(TM)
intervention type: Biological
intervention name: Commercial Hepatitis B vaccine
description: Commercially available prophylactic hepatitis B vaccine formulated with alum adjuvant
arm group label: Standard vaccine
other name: Engerix B
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Nikolai Petrovsky, MBBS/PhD
role: Study Director
affiliation: Vaxine Pty Ltd
last name: Sharen Pringle, RN
phone: 0437033400
email: admin@arasmi.org
facility: 
contact: 
investigator: 
country: Australia
responsible party type: Sponsor
mesh term: Hepatitis A
mesh term: Hepatitis B
mesh term: Hepatitis B, Chronic
mesh term: Virus Diseases
mesh term: Herpesviridae Infections
mesh term: Hepatitis
mesh term: Hepatitis, Chronic
mesh term: Vaccines
sharing ipd: Undecided