<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/NCT04490512</url>
  </required_header>
  <id_info>
    <org_study_id>BS-01</org_study_id>
    <nct_id>NCT04490512</nct_id>
  </id_info>
  <brief_title>Study of FluBHPVE6E7 in HPV-16 Infected Women</brief_title>
  <official_title>Randomised, Double-blind, Placebo-controlled Phase 1 Dose-escalation Study of FluBHPVE6E7 in HPV-16 Infected Women With Normal Cytology, CIN1 or CIN2</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>BlueSky Immunotherapies GmbH</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>BlueSky Immunotherapies GmbH</source>
  <oversight_info>
    <has_dmc>Yes</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>
      BS-01 is a randomised, double-blind, placebo-controlled, phase 1 dose escalation study&#xD;
      assessing safety, tolerability and immunogenicity of FluBHPVE6E7, changes in the HPV&#xD;
      infection status and cervical cytology, and biodistribution in HPV-16 infected women with&#xD;
      normal cytology, CIN1 or CIN2. The safety and immunogenicity of two dose levels, 7.5 log10&#xD;
      and 9.0 log10 fTCID50/dose of FluBHPVE6E7 are assessed after three subcutaneous&#xD;
      administrations. In addition the safety of 9.0 log10 fTCID50/dose of FluBHPVE6E7 is assessed&#xD;
      after three intradermal or intramuscular administrations.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      BS-01 is a randomised, placebo-controlled, double- blind phase 1 dose-escalation study in&#xD;
      women with normal cytology, CIN1 or CIN2.&#xD;
&#xD;
      The primary objective is to assess the safety and tolerability of FluBHPVE6E7. Secondary&#xD;
      objectives are the assessment of the systemic immune responses to immunisations with&#xD;
      FluBHPVE6E7, changes in HPV infection status and cervical cytology, and biodistribution.&#xD;
&#xD;
      Study medication is administered three times (Day 0, Week 4, Week 12). Study participants are&#xD;
      randomised at a ratio of 3:1 for FluBHPVE6E7 or placebo. The first cohort is treated&#xD;
      subcutaneously at dose level 7.5 log10 fTCID50/dose. The second cohort is treated&#xD;
      subcutaneously at 9.0 log10 fTCID50/dose.&#xD;
&#xD;
      Interim safety reviews are performed by a Data Monitoring Committee. After completion of the&#xD;
      dose-escalation and in order to collect additional safety data on the highest safe and&#xD;
      tolerated dose level, additional study participants are enrolled into expansion cohorts&#xD;
      treated three times subcutaneously, intradermally or intramuscularly at 9.0 log10&#xD;
      fTCID50/dose.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 9, 2020</start_date>
  <completion_date type="Actual">June 6, 2023</completion_date>
  <primary_completion_date type="Actual">March 16, 2023</primary_completion_date>
  <phase>Phase 1</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>Double-blind</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Number of participants with adverse events (type, frequency, severity).</measure>
    <time_frame>7 days</time_frame>
    <description>To assess the safety and tolerability of FluBHPVE6E7 by monitoring the type, frequency, and severity of AEs</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Hemagglutination Inhibition (HAI) Geometric Mean Titers (GMTs) following FluBHPVE6E7 administration</measure>
    <time_frame>16 weeks</time_frame>
    <description>To evaluate of the induction of systemic vector-specific antibodies by HAI assay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Induction of HPV-specific T-cell response following FluBHPVE6E7 administration</measure>
    <time_frame>16 weeks</time_frame>
    <description>To evaluate the induction of HPV16 E6- and E7-specific T-cells (%) by IFN-gamma ELISPOT analysis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Induction of HPV-specific CD4+ and CD8+ T-cells following FluBHPVE6E7 administration</measure>
    <time_frame>16 weeks</time_frame>
    <description>To evaluate the induction of HPV16 E6- and E7 specific T-cells (%) by ICS and FACS analysis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Local HPV clearance</measure>
    <time_frame>16 weeks</time_frame>
    <description>To evaluate the status of HPV-16 infection by HPV test (yes or no)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cervical cytology</measure>
    <time_frame>16 weeks</time_frame>
    <description>To evaluate changes in cervical cytology by Pap smear. Results are reported as Pap results according to the Bethesda System</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biodistribution: Detection of FluBHPVE6E7 in blood samples</measure>
    <time_frame>16 weeks</time_frame>
    <description>To evaluate the presence of FluBHPVE6E7 by quantification of FluBHPVE6E7 genome copies in blood samples by RT-qPCR (copies per ml blood)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biodistribution: Detection of FluBHPVE6E7 in nasal secretions</measure>
    <time_frame>16 weeks</time_frame>
    <description>To evaluate the presence of FluBHPVE6E7 by qualitative real-time PCR assay specific for influenza B virus (positive or negative)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with adverse events (type, frequency, severity).</measure>
    <time_frame>16 weeks</time_frame>
    <description>To assess the safety and tolerability of FluBHPVE6E7 by monitoring the type, frequency, and severity of AEs</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">28</enrollment>
  <condition>HPV Infection</condition>
  <arm_group>
    <arm_group_label>FluBHPVE6E7</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Multiple administration of FluBHPVE6E7</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Multiple administration of buffer solution</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>FluBHPVE6E7</intervention_name>
    <description>Multiple subcutaneous, intradermal or intramuscular administrations</description>
    <arm_group_label>FluBHPVE6E7</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Placebo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          -  Females in general good health, EITHER 18-49 years of age with HPV-16 infection and&#xD;
             cervical cytological evaluation with a normal result, OR 25-49 years of age, with&#xD;
             HPV-16 infection, and histologically confirmed cervical intraepithelial neoplasia 1&#xD;
             (CIN1) or 2 (CIN2) for whom a &quot;wait-and-see&quot; approach for the study period is&#xD;
             indicated&#xD;
&#xD;
          -  HPV-16 infection has been confirmed at least twice by a validated HPV test separated&#xD;
             by at least 3 months&#xD;
&#xD;
          -  Satisfactory colposcopy (i.e. the entire cervix as well as the entire squamocolumnar&#xD;
             junction can be visualized by colposcopy and there is no evidence of invasive cancer)&#xD;
&#xD;
          -  No clinically significant out of range haematological, renal or hepatic laboratory&#xD;
             tests&#xD;
&#xD;
          -  Normal screening ECG or screening ECG with no clinically significant findings, as&#xD;
             judged by the investigator&#xD;
&#xD;
          -  Negative serum pregnancy test at screening&#xD;
&#xD;
          -  Agree to use a reliable form of contraception during the whole study period. Reliable&#xD;
             forms of contraception are hysterectomy or bilateral tubal ligation, hormonal methods&#xD;
             (oral, injected, implanted or transdermal), intrauterine device, barrier method plus&#xD;
             spermicide, history of a single male partner with vasectomy, or a history of&#xD;
             abstinence deemed credible by the investigator. Furthermore, male partners should use&#xD;
             condoms during the whole study period.&#xD;
&#xD;
          -  Provides written informed consent&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  Seropositivity (i.e. HAI titres &gt;1:20) to the vector-derived wild type virus&#xD;
&#xD;
          -  Any vaccination within 6 weeks of receiving study treatment&#xD;
&#xD;
          -  Active significant viral infections including influenza, CMV, and EBV within 30 days&#xD;
             of receiving study treatment&#xD;
&#xD;
          -  Current cervical intraepithelial neoplasia 3 (CIN3)&#xD;
&#xD;
          -  Co-infection with hepatitis B, hepatitis C, or HIV or having other immune deficient&#xD;
             states&#xD;
&#xD;
          -  Prior history of or current malignancy, high-grade cervical intraepithelial neoplasia&#xD;
             (CIN2/3), vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia&#xD;
             (VAIN), atypical glandular cells (AGC), adenocarcinoma in situ (AIS) or any suspicion&#xD;
             of either micro-invasive or invasive disease&#xD;
&#xD;
          -  Pregnancy, breastfeeding&#xD;
&#xD;
          -  Influenza-like illness (ILI) during the preceding 3 months&#xD;
&#xD;
          -  Known hypersensitivity to oseltamivir or any of its components&#xD;
&#xD;
          -  Any anatomical condition of the cervix, including that resulting from previous&#xD;
             cervical surgery, congenital malformation or other condition, that would interfere&#xD;
             with a complete evaluation of the cervix&#xD;
&#xD;
          -  Current pelvic inflammatory disease, cervicitis, or other gynaecological infection as&#xD;
             per colposcopy and clinical examination&#xD;
&#xD;
          -  Serious, concomitant disorder, including active systemic infection requiring treatment&#xD;
&#xD;
          -  Presence of acute or chronic bleeding or clotting disorder, or use of blood thinners&#xD;
             (e.g. anticoagulants or antiplatelet drugs) within 2 weeks of day 0&#xD;
&#xD;
          -  A proven or suspected autoimmune disease&#xD;
&#xD;
          -  Immunosuppression including any concurrent condition requiring the continued use of&#xD;
             systemic or topical steroids, or the use of immunosuppressive agents, disease&#xD;
             modifying doses of anti-rheumatic drugs (e.g., azathioprine, cyclophosphamide,&#xD;
             cyclosporine, methotrexate), and biologic disease modifying drugs such as TNF-α&#xD;
             inhibitors (e.g. infliximab, adalimumab or etanercept). Corticosteroids must be&#xD;
             discontinued &gt; 4 weeks prior to day 0 of study medication administration. Eye drops or&#xD;
             ear drops containing corticosteroids are permissible.&#xD;
&#xD;
          -  Acute or history of Herpes genitalis&#xD;
&#xD;
          -  Prior major surgery within 4 weeks of day 0&#xD;
&#xD;
          -  Administration of any blood product within 3 months of enrolment&#xD;
&#xD;
          -  Any current significant cardiac, hepatic or renal disease or history of clinically&#xD;
             significant, medically unstable disease (e.g. chronic renal failure; angina,&#xD;
             myocardial ischemia or infarction, congestive heart failure, cardiomyopathy, or&#xD;
             clinically significant arrhythmias)&#xD;
&#xD;
          -  Any current or history of neurological disease including history of seizures&#xD;
&#xD;
          -  Participation in another experimental protocol/use of investigational drug during the&#xD;
             prior two months&#xD;
&#xD;
          -  Any condition that, in the judgment of the investigator, might prevent safe&#xD;
             participation in the study or interfere with study objectives&#xD;
&#xD;
          -  Unability to comply with the protocol requirements&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>49 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Medical University of Vienna</name>
      <address>
        <city>Vienna</city>
        <zip>1090</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Austria</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>June 30, 2020</study_first_submitted>
  <study_first_submitted_qc>July 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 29, 2020</study_first_posted>
  <last_update_submitted>June 23, 2023</last_update_submitted>
  <last_update_submitted_qc>June 23, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 26, 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>Papillomavirus Infections</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/NCT04490512
org study id: BS-01
nct id: NCT04490512
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
BS-01 is a randomised, double-blind, placebo-controlled, phase 1 dose escalation study
      assessing safety, tolerability and immunogenicity of FluBHPVE6E7, changes in the HPV
      infection status and cervical cytology, and biodistribution in HPV-16 infected women with
      normal cytology, CIN1 or CIN2. The safety and immunogenicity of two dose levels, 7.5 log10
      and 9.0 log10 fTCID50/dose of FluBHPVE6E7 are assessed after three subcutaneous
      administrations. In addition the safety of 9.0 log10 fTCID50/dose of FluBHPVE6E7 is assessed
      after three intradermal or intramuscular administrations.
BS-01 is a randomised, placebo-controlled, double- blind phase 1 dose-escalation study in
      women with normal cytology, CIN1 or CIN2.

      The primary objective is to assess the safety and tolerability of FluBHPVE6E7. Secondary
      objectives are the assessment of the systemic immune responses to immunisations with
      FluBHPVE6E7, changes in HPV infection status and cervical cytology, and biodistribution.

      Study medication is administered three times (Day 0, Week 4, Week 12). Study participants are
      randomised at a ratio of 3:1 for FluBHPVE6E7 or placebo. The first cohort is treated
      subcutaneously at dose level 7.5 log10 fTCID50/dose. The second cohort is treated
      subcutaneously at 9.0 log10 fTCID50/dose.

      Interim safety reviews are performed by a Data Monitoring Committee. After completion of the
      dose-escalation and in order to collect additional safety data on the highest safe and
      tolerated dose level, additional study participants are enrolled into expansion cohorts
      treated three times subcutaneously, intradermally or intramuscularly at 9.0 log10
      fTCID50/dose.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
masking description: Double-blind
measure: Number of participants with adverse events (type, frequency, severity).
time frame: 7 days
description: To assess the safety and tolerability of FluBHPVE6E7 by monitoring the type, frequency, and severity of AEs
measure: Hemagglutination Inhibition (HAI) Geometric Mean Titers (GMTs) following FluBHPVE6E7 administration
time frame: 16 weeks
description: To evaluate of the induction of systemic vector-specific antibodies by HAI assay
measure: Induction of HPV-specific T-cell response following FluBHPVE6E7 administration
time frame: 16 weeks
description: To evaluate the induction of HPV16 E6- and E7-specific T-cells (%) by IFN-gamma ELISPOT analysis
measure: Induction of HPV-specific CD4+ and CD8+ T-cells following FluBHPVE6E7 administration
time frame: 16 weeks
description: To evaluate the induction of HPV16 E6- and E7 specific T-cells (%) by ICS and FACS analysis
measure: Local HPV clearance
time frame: 16 weeks
description: To evaluate the status of HPV-16 infection by HPV test (yes or no)
measure: Cervical cytology
time frame: 16 weeks
description: To evaluate changes in cervical cytology by Pap smear. Results are reported as Pap results according to the Bethesda System
measure: Biodistribution: Detection of FluBHPVE6E7 in blood samples
time frame: 16 weeks
description: To evaluate the presence of FluBHPVE6E7 by quantification of FluBHPVE6E7 genome copies in blood samples by RT-qPCR (copies per ml blood)
measure: Biodistribution: Detection of FluBHPVE6E7 in nasal secretions
time frame: 16 weeks
description: To evaluate the presence of FluBHPVE6E7 by qualitative real-time PCR assay specific for influenza B virus (positive or negative)
measure: Number of participants with adverse events (type, frequency, severity).
time frame: 16 weeks
description: To assess the safety and tolerability of FluBHPVE6E7 by monitoring the type, frequency, and severity of AEs
arm group label: FluBHPVE6E7
arm group type: Experimental
description: Multiple administration of FluBHPVE6E7
arm group label: Placebo
arm group type: Placebo Comparator
description: Multiple administration of buffer solution
intervention type: Biological
intervention name: FluBHPVE6E7
description: Multiple subcutaneous, intradermal or intramuscular administrations
arm group label: FluBHPVE6E7
arm group label: Placebo
other name: Placebo
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 49 Years
healthy volunteers: No
facility: 
country: Austria
responsible party type: Sponsor
mesh term: Papillomavirus Infections