<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/NCT02233075</url>
  </required_header>
  <id_info>
    <org_study_id>REP 301</org_study_id>
    <nct_id>NCT02233075</nct_id>
  </id_info>
  <brief_title>REP 2139-Ca / Pegasys™ Combination Therapy in Hepatitis B / Hepatitis D Co-infection</brief_title>
  <official_title>A Study of the Safety and Efficacy of Combination Treatment With REP 2139-Ca and Pegasys™ in Patients With Hepatitis B / Hepatitis D Co-infection</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Replicor Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Replicor Inc.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      REP 2139-Ca is nucleic acid polymer. Nucleic acid polymers have been previously shown to&#xD;
      clear serum hepatitis B virus surface antigen (HBsAg) both preclinically (in duck HBV&#xD;
      infected ducks) and in human patients and to act synergistically with immunotherapeutic&#xD;
      agents such as pegylated interferon-alpha 2a or thymosin alpha-1 to restore host&#xD;
      immunological control of HBV infection.&#xD;
&#xD;
      HBsAg is an essential component of the hepatitis D virus (HDV), therefore the direct action&#xD;
      of REP 2139-Ca in removing serum HBsAg and its synergistic effect with pegylated&#xD;
      interferon-alpha 2a is expected to have a significant antiviral effect against HDV infection.&#xD;
&#xD;
      This study will examine the safety and efficacy of REP 2139-Ca therapy when used in&#xD;
      combination with pegylated interferon alpha-2a in patients with HBV / HDV co-infection.&#xD;
&#xD;
      The primary hypothesis to be tested is that this combined dosing regimen is safe and well&#xD;
      tolerated in patients with HBV / HDV co-infection which will be assessed by examining the&#xD;
      number of patients with adverse events (including reported symptoms and laboratory&#xD;
      abnormalities).&#xD;
&#xD;
      The secondary hypothesis to be tested is that this combined dosing regimen will have an&#xD;
      antiviral effect against HBV / HDV co-infection in these patients which will be assessed by&#xD;
      examining the following outcomes:&#xD;
&#xD;
        1. The number of patients with reductions in serum HBsAg.&#xD;
&#xD;
        2. The number of patients with reductions in serum HDAg and HDV RNA&#xD;
&#xD;
        3. The number of patients that experience a sustained antiviral response after treatment is&#xD;
           stopped (reductions in serum HBV DNA and HDV RNA).&#xD;
&#xD;
      The secondary hypothesis to be tested is that this combination approach can have an effective&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Nucleic acid polymers (NAPs) utilize the sequence independent properties of phosphorothioated&#xD;
      oligonucleotides to target apolipoprotein interactions involved in the formation of HBV&#xD;
      subviral particles (SVPs) which are comprised mainly of the hepatitis B surface antigen&#xD;
      protein (HBsAg). The effect of NAPs is to block the formation of SVPs inside infected&#xD;
      hepatocytes which prevents their secretion. As SVPs account for &gt; 99.99% of HBsAg in the&#xD;
      blood, NAPs are an effective approach for clearing HBsAg from the serum of HBV infected&#xD;
      patient.&#xD;
&#xD;
      Previous clinical trials have demonstrated that treatment with the NAP REP 2139 results in&#xD;
      the rapid and effective clearance of HBsAg from the blood. This HBsAg removal has the&#xD;
      immediate effect of unmasking the underlying, pre-existing anti-HBsAg (anti-HBs) response,&#xD;
      allowing clearance of HBV virus from the blood.&#xD;
&#xD;
      HBsAg has important immunosuppressive effects in HBV infection which have been shown to block&#xD;
      both adaptive and innate immune processes. Removal of HBsAg from the blood of patients&#xD;
      removes this immunosuppressive effect.&#xD;
&#xD;
      Thus, an important additional effect of removal of HBsAg from the blood is to greatly enhance&#xD;
      the effect of immunotherapeutic agents like pegylated interferon alpha-2a or thymosin alpha-1&#xD;
      to stimulate recovery of complete immune control of HBV infection.&#xD;
&#xD;
      HDV superinfection can only occur in patients with HBV infection because HDV requires the&#xD;
      HBsAg protein for its assembly. Therefore, it is expected that the removal of serum HBsAg&#xD;
      (from HBV SVPs) and unmasking of the anticipated, pre-existing anti-HBsAg response by REP&#xD;
      2139 will result in the clearance of HBV and HDV from the blood. Furthermore, the enhanced&#xD;
      effect of immunotherapy in the absence of serum HBsAg has the potential to provide a durable&#xD;
      control of both HBV and HDV infection that will persist after treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2014</start_date>
  <completion_date type="Actual">May 2017</completion_date>
  <primary_completion_date type="Actual">November 2016</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of patients experiencing a treatment-related adverse event.</measure>
    <time_frame>Every week for 63 weeks.</time_frame>
    <description>Will examine the hypothesis that combined REP 2139-Ca / Pegasys(TM) treatment is safe and well tolerated in patients with HBV / HDV co-infection</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of patients with reduction of serum HBsAg.</measure>
    <time_frame>Every two weeks for 63 weeks (treatment duration) + 24 weeks (follow-up)</time_frame>
    <description>Will examine the hypothesis that combination treatment with REP 2139-Ca / Pegasys(TM) will have an antiviral effect in patients with HBV / HDV co-infection.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients with reduced serum HDV antigen / HDV RNA</measure>
    <time_frame>Every two weeks for 63 weeks (treatment duration) + 24 weeks followup</time_frame>
    <description>Will examine the hypothesis that combination treatment with REP 2139-Ca / Pegasys(TM) will have an antiviral effect in patients with HBV / HDV co-infection.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients with controlled HBV / HDV infection following treatment</measure>
    <time_frame>24 weeks follow up (after completion of 63 weeks of treatment)</time_frame>
    <description>Will examine the hypothesis that combination treatment with REP 2139-Ca / Pegasys(TM) will have an antiviral effect in patients with HBV / HDV co-infection.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>Chronic HBV Infection (HBeAg Negative)</condition>
  <arm_group>
    <arm_group_label>REP 2139-Ca + Pegasys (TM)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>REP 2139-Ca 500 mg QW for 15 weeks followed by REP 2139-Ca 250mg QW + Pegasys(TM) 180ug QW for 15 weeks followed by Pegasys(TM) 180ug QW for 33 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>REP 2139-Ca + Pegasys (TM)</intervention_name>
    <description>15 weeks of REP 2139-Ca (500mg QW IV) followed by: 15 weeks of REP 2139-Ca (250mg QW IV) + Pegasys(TM) (180 ug QW SC) followed by: 33 weeks of Pegasys(TM) (180 ug QW SC)</description>
    <arm_group_label>REP 2139-Ca + Pegasys (TM)</arm_group_label>
    <other_name>Pegasys(TM) = pegylated interferon alpha-2a</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age between 18 and 55 years&#xD;
&#xD;
          -  HBsAg &gt; 1000 IU / ml&#xD;
&#xD;
          -  HDAg+&#xD;
&#xD;
          -  HDV RNA +&#xD;
&#xD;
          -  No detectable antibodies to HIV, HCV or CMV.&#xD;
&#xD;
          -  Non cirrhotic&#xD;
&#xD;
          -  Willingness to utilize adequate contraception while being treated with REP 213-Ca and&#xD;
             for 6 months following the end of treatment&#xD;
&#xD;
          -  Adequate venous access allowing weekly intravenous therapies and blood tests&#xD;
&#xD;
          -  Body Mass Index (BMI) ≥ 18 kg/m2 and ≤ 25 kg/m2&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Evidence of cardiovascular disease&#xD;
&#xD;
          -  Evidence of autoimmune hepatitis&#xD;
&#xD;
          -  Presence of Wilson's disease&#xD;
&#xD;
          -  Presence of severe NAFLD&#xD;
&#xD;
          -  Evidence of any other co-existent liver disease&#xD;
&#xD;
          -  ANA (anti-nuclear antibody) positive&#xD;
&#xD;
          -  Fibroscan and Fibromax showing evidence of advanced cirrhosis.&#xD;
&#xD;
          -  Any history of ascites, hepatic encephalopathy or variceal hemorrhage&#xD;
&#xD;
          -  Body weight &gt; 100 kg&#xD;
&#xD;
          -  Platelet count &lt; 90,000, PMN count &lt; 1,500 or HCT &lt; 33%&#xD;
&#xD;
          -  Evidence of significant heavy metal load in whole blood.&#xD;
&#xD;
          -  AFP &gt; 100 ng/ml or the presence of a hepatic mass suggestive of HCC&#xD;
&#xD;
          -  Bilirubin above the normal range&#xD;
&#xD;
          -  ALT &gt; 5x ULN&#xD;
&#xD;
          -  Creatinine &gt; 1.5 mg/dl&#xD;
&#xD;
          -  Serum albumin &lt; 35 mg/ml&#xD;
&#xD;
          -  The presence of diabetes (whether controlled or uncontrolled)&#xD;
&#xD;
          -  Another serious medical disorder&#xD;
&#xD;
          -  A serious psychiatric disorder&#xD;
&#xD;
          -  Evidence of hypertension&#xD;
&#xD;
          -  A history of alcohol abuse within the last year&#xD;
&#xD;
          -  The use of illicit drugs within the past two years&#xD;
&#xD;
          -  Inability to provide informed consent&#xD;
&#xD;
          -  Inability or unwillingness to provide weekly blood samples&#xD;
&#xD;
          -  Poor venous access making IV infusion too difficult&#xD;
&#xD;
          -  Patient not willing to come every week to receive therapy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Victor Pantea, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Infectious Diseases Department, State University of Medicine and Pharmacy</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Infectious Clinical Hospital ( n.a. Toma Ciorba)</name>
      <address>
        <city>Chisinau</city>
        <zip>2004</zip>
        <country>Moldova, Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Moldova, Republic of</country>
  </location_countries>
  <reference>
    <citation>Noordeen F, Vaillant A, Jilbert AR. Nucleic acid polymers inhibit duck hepatitis B virus infection in vitro. Antimicrob Agents Chemother. 2013 Nov;57(11):5291-8. doi: 10.1128/AAC.01003-13. Epub 2013 Aug 12.</citation>
    <PMID>23939902</PMID>
  </reference>
  <reference>
    <citation>Noordeen F, Vaillant A, Jilbert AR. Nucleic acid polymers prevent the establishment of duck hepatitis B virus infection in vivo. Antimicrob Agents Chemother. 2013 Nov;57(11):5299-306. doi: 10.1128/AAC.01005-13. Epub 2013 Aug 12.</citation>
    <PMID>23939904</PMID>
  </reference>
  <verification_date>February 2017</verification_date>
  <study_first_submitted>September 1, 2014</study_first_submitted>
  <study_first_submitted_qc>September 5, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 8, 2014</study_first_posted>
  <last_update_submitted>September 26, 2017</last_update_submitted>
  <last_update_submitted_qc>September 26, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 28, 2017</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>Infections</mesh_term>
    <mesh_term>Communicable Diseases</mesh_term>
    <mesh_term>Hepatitis B</mesh_term>
    <mesh_term>Coinfection</mesh_term>
    <mesh_term>Hepatitis D</mesh_term>
    <mesh_term>Hepatitis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Interferons</mesh_term>
    <mesh_term>Interferon-alpha</mesh_term>
    <mesh_term>Interferon alpha-2</mesh_term>
    <mesh_term>Peginterferon alfa-2a</mesh_term>
    <mesh_term>REP 2139</mesh_term>
  </intervention_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/NCT02233075
org study id: REP 301
nct id: NCT02233075
lead sponsor: 
has dmc: No
REP 2139-Ca is nucleic acid polymer. Nucleic acid polymers have been previously shown to
      clear serum hepatitis B virus surface antigen (HBsAg) both preclinically (in duck HBV
      infected ducks) and in human patients and to act synergistically with immunotherapeutic
      agents such as pegylated interferon-alpha 2a or thymosin alpha-1 to restore host
      immunological control of HBV infection.

      HBsAg is an essential component of the hepatitis D virus (HDV), therefore the direct action
      of REP 2139-Ca in removing serum HBsAg and its synergistic effect with pegylated
      interferon-alpha 2a is expected to have a significant antiviral effect against HDV infection.

      This study will examine the safety and efficacy of REP 2139-Ca therapy when used in
      combination with pegylated interferon alpha-2a in patients with HBV / HDV co-infection.

      The primary hypothesis to be tested is that this combined dosing regimen is safe and well
      tolerated in patients with HBV / HDV co-infection which will be assessed by examining the
      number of patients with adverse events (including reported symptoms and laboratory
      abnormalities).

      The secondary hypothesis to be tested is that this combined dosing regimen will have an
      antiviral effect against HBV / HDV co-infection in these patients which will be assessed by
      examining the following outcomes:

        1. The number of patients with reductions in serum HBsAg.

        2. The number of patients with reductions in serum HDAg and HDV RNA

        3. The number of patients that experience a sustained antiviral response after treatment is
           stopped (reductions in serum HBV DNA and HDV RNA).

      The secondary hypothesis to be tested is that this combination approach can have an effective
Nucleic acid polymers (NAPs) utilize the sequence independent properties of phosphorothioated
      oligonucleotides to target apolipoprotein interactions involved in the formation of HBV
      subviral particles (SVPs) which are comprised mainly of the hepatitis B surface antigen
      protein (HBsAg). The effect of NAPs is to block the formation of SVPs inside infected
      hepatocytes which prevents their secretion. As SVPs account for > 99.99% of HBsAg in the
      blood, NAPs are an effective approach for clearing HBsAg from the serum of HBV infected
      patient.

      Previous clinical trials have demonstrated that treatment with the NAP REP 2139 results in
      the rapid and effective clearance of HBsAg from the blood. This HBsAg removal has the
      immediate effect of unmasking the underlying, pre-existing anti-HBsAg (anti-HBs) response,
      allowing clearance of HBV virus from the blood.

      HBsAg has important immunosuppressive effects in HBV infection which have been shown to block
      both adaptive and innate immune processes. Removal of HBsAg from the blood of patients
      removes this immunosuppressive effect.

      Thus, an important additional effect of removal of HBsAg from the blood is to greatly enhance
      the effect of immunotherapeutic agents like pegylated interferon alpha-2a or thymosin alpha-1
      to stimulate recovery of complete immune control of HBV infection.

      HDV superinfection can only occur in patients with HBV infection because HDV requires the
      HBsAg protein for its assembly. Therefore, it is expected that the removal of serum HBsAg
      (from HBV SVPs) and unmasking of the anticipated, pre-existing anti-HBsAg response by REP
      2139 will result in the clearance of HBV and HDV from the blood. Furthermore, the enhanced
      effect of immunotherapy in the absence of serum HBsAg has the potential to provide a durable
      control of both HBV and HDV infection that will persist after treatment.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of patients experiencing a treatment-related adverse event.
time frame: Every week for 63 weeks.
description: Will examine the hypothesis that combined REP 2139-Ca / Pegasys(TM) treatment is safe and well tolerated in patients with HBV / HDV co-infection
measure: Number of patients with reduction of serum HBsAg.
time frame: Every two weeks for 63 weeks (treatment duration) + 24 weeks (follow-up)
description: Will examine the hypothesis that combination treatment with REP 2139-Ca / Pegasys(TM) will have an antiviral effect in patients with HBV / HDV co-infection.
measure: Number of patients with reduced serum HDV antigen / HDV RNA
time frame: Every two weeks for 63 weeks (treatment duration) + 24 weeks followup
description: Will examine the hypothesis that combination treatment with REP 2139-Ca / Pegasys(TM) will have an antiviral effect in patients with HBV / HDV co-infection.
measure: Number of patients with controlled HBV / HDV infection following treatment
time frame: 24 weeks follow up (after completion of 63 weeks of treatment)
description: Will examine the hypothesis that combination treatment with REP 2139-Ca / Pegasys(TM) will have an antiviral effect in patients with HBV / HDV co-infection.
arm group label: REP 2139-Ca + Pegasys (TM)
arm group type: Experimental
description: REP 2139-Ca 500 mg QW for 15 weeks followed by REP 2139-Ca 250mg QW + Pegasys(TM) 180ug QW for 15 weeks followed by Pegasys(TM) 180ug QW for 33 weeks.
intervention type: Drug
intervention name: REP 2139-Ca + Pegasys (TM)
description: 15 weeks of REP 2139-Ca (500mg QW IV) followed by: 15 weeks of REP 2139-Ca (250mg QW IV) + Pegasys(TM) (180 ug QW SC) followed by: 33 weeks of Pegasys(TM) (180 ug QW SC)
arm group label: REP 2139-Ca + Pegasys (TM)
other name: Pegasys(TM) = pegylated interferon alpha-2a
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: No
last name: Victor Pantea, MD
role: Principal Investigator
affiliation: Infectious Diseases Department, State University of Medicine and Pharmacy
facility: 
country: Moldova, Republic of
citation: Noordeen F, Vaillant A, Jilbert AR. Nucleic acid polymers inhibit duck hepatitis B virus infection in vitro. Antimicrob Agents Chemother. 2013 Nov;57(11):5291-8. doi: 10.1128/AAC.01003-13. Epub 2013 Aug 12.
PMID: 23939902
citation: Noordeen F, Vaillant A, Jilbert AR. Nucleic acid polymers prevent the establishment of duck hepatitis B virus infection in vivo. Antimicrob Agents Chemother. 2013 Nov;57(11):5299-306. doi: 10.1128/AAC.01005-13. Epub 2013 Aug 12.
PMID: 23939904
responsible party type: Sponsor
mesh term: Infections
mesh term: Communicable Diseases
mesh term: Hepatitis B
mesh term: Coinfection
mesh term: Hepatitis D
mesh term: Hepatitis
mesh term: Interferons
mesh term: Interferon-alpha
mesh term: Interferon alpha-2
mesh term: Peginterferon alfa-2a
mesh term: REP 2139