<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/NCT03265977</url>
  </required_header>
  <id_info>
    <org_study_id>A-043</org_study_id>
    <nct_id>NCT03265977</nct_id>
  </id_info>
  <brief_title>A Phase II Study of H56:IC31 in Healthy Adolescents</brief_title>
  <acronym>A-043</acronym>
  <official_title>A Randomized, Placebo Controlled, Double-Blind Phase II Study to Evaluate Safety, Immunogenicity, and Prevention of Infection With Mycobacterium Tuberculosis (Mtb) of H56:IC31 in Healthy Adolescents</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Aeras</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Statens Serum Institut</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Aurum Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>South African Tuberculosis Vaccine Initiative</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Oslo University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Copenhagen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Bergen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute for Medical Research, Tanzania</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Aeras</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>
      This clinical trial will evaluate safety, immunogenicity, and efficacy (prevention of Mtb&#xD;
      infection as measured by IGRA conversions) of H56:IC31 in remotely BCG vaccinated&#xD;
      adolescents.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This clinical trial will evaluate safety, immunogenicity, and prevention of Mtb infection,&#xD;
      (measured by IGRA conversion) of H56:IC31 in remotely BCG vaccinated adolescents. A TB&#xD;
      vaccination strategy incorporating H56:IC31 in adolescents or young adults, if found to&#xD;
      prevent Mtb infection, would likely have a major impact on TB disease, TB transmission, and&#xD;
      control of the epidemic. If vaccination with H56:IC31 is shown to prevent infection with Mtb&#xD;
      in this proof of concept study in adolescents, additional larger scale studies examining the&#xD;
      impact on TB disease in more diverse populations would be warranted.&#xD;
&#xD;
      Primary objectives&#xD;
&#xD;
        -  To evaluate the safety profile of H56:IC31 compared to placebo in HIV-uninfected,&#xD;
           remotely BCG vaccinated adolescents.&#xD;
&#xD;
        -  To evaluate prevention of Mtb infection by H56:IC31 compared to placebo, as measured by&#xD;
           rates of conversion using an ESAT-6 free IGRA.&#xD;
&#xD;
      Secondary objectives&#xD;
&#xD;
        -  To evaluate prevention of Mtb infection by H56:IC31 compared to placebo, as measured by&#xD;
           rates of sustained conversion using an ESAT-6 free IGRA.&#xD;
&#xD;
        -  To evaluate trends in ESAT-6 free IGRA prolonged/sustained conversions and late&#xD;
           reversions (i.e., through more than 6 months post initial conversion) in ESAT-6 free&#xD;
           IGRA converters.&#xD;
&#xD;
        -  To investigate the immunogenicity of H56:IC31 in HIV-uninfected, remotely BCG vaccinated&#xD;
           adolescents.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Design, sponsorship changed prior to initiation. No study procedures done.&#xD;
  </why_stopped>
  <start_date type="Anticipated">June 2018</start_date>
  <completion_date type="Anticipated">June 30, 2021</completion_date>
  <primary_completion_date type="Anticipated">April 30, 2021</primary_completion_date>
  <phase>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>
    <intervention_model_description>Participants will be enrolled in two cohorts. Within each cohort participants will be randomized in a 1:1 ratio to receive either H56:IC31 (5 ug H56/500 nmol IC31) or placebo intramuscularly (IM) on Days 0 and 56.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>Random numbers generated by IWRS; Stratified by site. Syringes are masked with a translucent colored label, in order to maintain the study blind.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Frequency and severity of adverse events</measure>
    <time_frame>Day 0 through month 24</time_frame>
    <description>To evaluate the safety profile of H56:IC31 compared to placebo in HIV-uninfected, previously BCG vaccinated adolescents.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>ESAT-6 free IGRA conversion from a negative to positive test at any time point after Day 84 and through end of follow-up for the primary endpoint.</measure>
    <time_frame>Day 84 through month 24</time_frame>
    <description>To evaluate prevention of Mtb infection by H56:IC31 compared to placebo, as measured by rates of conversion using an ESAT-6 free IGRA.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Primary ESAT-6 free IGRA conversion from a negative to a positive test</measure>
    <time_frame>Day 84 through month 24</time_frame>
    <description>Primary ESAT-6 free IGRA conversion from a negative to a positive test at any time point after Day 84 and through end of follow up for the primary endpoint, AND persisting without ESAT-6 free IGRA reversion from a positive to a negative test through 6 months after ESAT-6 free IGRA conversion.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Primary ESAT-6 free IGRA conversion from a negative to a positive test</measure>
    <time_frame>Day 84 through end of study (approximately 24 months)</time_frame>
    <description>Primary ESAT-6 free IGRA conversion from a negative to a positive test at any time point after randomization and through end of follow up for the primary endpoint, AND persisting without ESAT-6 free IGRA reversion from a positive to a negative test through 6 months after ESAT-6 free IGRA conversion.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Initial ESAT-6 free IGRA reversion from a positive to a negative test at any time point after primary ESAT-6 free IGRA conversion through the end of follow up.</measure>
    <time_frame>Day 84 through month 24</time_frame>
    <description>To evaluate trends in ESAT-6 free IGRA prolonged/sustained conversions and late reversions (i.e., through more than 6 months post initial conversion) in ESAT-6 free IGRA converters.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of CD4+ and CD8+ T cells that express IFN-γ, TNF, and/or IL-2 alone or in combination in response to stimulation with peptide pools representing the entire amino acid sequence of the vaccine antigens.</measure>
    <time_frame>Day 0 through month 24</time_frame>
    <description>Immunogenicity of H56:IC31 in HIV-uninfected, previously BCG vaccinated adolescents.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Tuberculosis Infection</condition>
  <arm_group>
    <arm_group_label>H56:IC31</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>5 ug H56/500 nmol IC31, 0.5 mL Intramuscular (IM), Days 0 and 56</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Normal saline, 0.5 mL IM, Days 0 and 56</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>H56:IC31</intervention_name>
    <description>The H56 antigen is a fusion protein created from 3 Mtb antigens: antigen 85B (Ag85B), ESAT-6, and Rv2660c.</description>
    <arm_group_label>H56:IC31</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Normal saline</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Has completed the written informed consent and assent process&#xD;
&#xD;
          2. Is age ≥12 years and ≤17 years on Study Day 0&#xD;
&#xD;
          3. Agrees to stay in contact with the study site for the duration of the study, provide&#xD;
             updated contact information as necessary, and has no current plans to move from the&#xD;
             study area for the duration of the study&#xD;
&#xD;
          4. For female participants: agrees to avoid pregnancy from 21 days prior to Study Day 0&#xD;
             through 6 months after the last study vaccination. Women physically capable of&#xD;
             pregnancy (not sterilized and still menstruating or within 1 year of the last menses)&#xD;
             in sexual relationships with men must use an acceptable method of avoiding pregnancy&#xD;
             during this period. Acceptable methods of avoiding pregnancy include a sterile sexual&#xD;
             partner, sexual abstinence (not engaging in sexual intercourse), hormonal&#xD;
             contraceptives (oral, injection, transdermal patch, or implant), vaginal ring, or&#xD;
             intrauterine device (IUD)&#xD;
&#xD;
          5. Has general good health, confirmed by medical history and physical examination&#xD;
&#xD;
          6. Had BCG vaccination at least 5 years ago documented by confirmation of parent/guardian&#xD;
             that the participant received all childhood vaccines or by presence of healed BCG scar&#xD;
&#xD;
          7. Tests ESAT-6 free IGRA and QFT-Plus negative at screening, using a pre-determined&#xD;
             threshold for ESAT-6 free IGRA and the manufacturer's recommended threshold for&#xD;
             QFT-Plus of 0.35 IU/mL in either of the TB antigen tubes after nil-subtraction&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Acute illness on Study Day 0&#xD;
&#xD;
          2. Axillary temperature ≥37.5 °C on Study Day 0&#xD;
&#xD;
          3. Abnormal laboratory values from the most recent blood collected prior to randomization&#xD;
             as follows (abnormal results may be repeated once and if found to be resolved the&#xD;
             participant will not be excluded):&#xD;
&#xD;
               -  Laboratory evidence of hematologic disease (white blood cell count &lt;3000/mm^3 or&#xD;
                  &gt;11,500/mm^3; hemoglobin &lt;0.9 times the lower limit of normal of the testing&#xD;
                  laboratory, by age and gender; absolute neutrophil count &lt;1300/mm^3; absolute&#xD;
                  lymphocyte count &lt;1000/mm^3).&#xD;
&#xD;
               -  ALT, AST, alkaline phosphatase, total bilirubin, creatinine, blood urea nitrogen&#xD;
                  (BUN) &gt;1.25 times the ULN&#xD;
&#xD;
          4. Urinalysis abnormality greater than Grade 1 on the Toxicity Scale (with the exception&#xD;
             of hematuria in a menstruating female), or urinalysis abnormality judged clinically&#xD;
             significant by the investigator&#xD;
&#xD;
          5. History or evidence of any clinically significant systemic disease, or any acute or&#xD;
             chronic illness that might affect the safety, immunogenicity, or efficacy of&#xD;
             investigational product in the opinion of the investigator&#xD;
&#xD;
          6. History of treatment for active TB disease or latent Mtb infection&#xD;
&#xD;
          7. History or evidence, including chest X-ray, of active TB disease&#xD;
&#xD;
          8. Shared household with an individual receiving anti-TB treatment, or known to have&#xD;
             incompletely treated culture or smear positive TB, at screening&#xD;
&#xD;
          9. History of autoimmune disease or immunosuppression&#xD;
&#xD;
         10. Used immunosuppressive medication within 42 days before Study Day 0 (inhaled and&#xD;
             topical corticosteroids are permitted)&#xD;
&#xD;
         11. Received immunoglobulin or blood products within 42 days before Study Day 0&#xD;
&#xD;
         12. Received any investigational drug or investigational vaccine within 180 days before&#xD;
             Study Day 0, or planned participation in any other clinical trial during the study&#xD;
             period&#xD;
&#xD;
         13. Received investigational TB vaccine at any time prior to Study Day 0&#xD;
&#xD;
         14. Planned administration/administration of a licensed vaccine in the period starting 28&#xD;
             days before and ending 28 days after each dose of investigational product&#xD;
&#xD;
         15. History or laboratory evidence of any past or present possible immunodeficiency state&#xD;
             including, but not limited to, any laboratory indication of HIV 1 infection&#xD;
&#xD;
         16. History of allergic disease or reactions, including eczema, likely to be exacerbated&#xD;
             by any component of the investigational product&#xD;
&#xD;
         17. History of alcohol or drug abuse&#xD;
&#xD;
         18. Any female currently pregnant or lactating/nursing, or positive urine pregnancy test&#xD;
             during screening or Study Day 0&#xD;
&#xD;
         19. Received a tuberculin skin test (TST) within 3 months (90 days) prior to Study Day 0.&#xD;
&#xD;
         20. Any current medical, psychiatric, occupational, or substance abuse problems that, in&#xD;
             the opinion of the investigator, will make it unlikely that the participant will&#xD;
             comply with the protocol.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>12 Years</minimum_age>
    <maximum_age>17 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Dereck Tait, MD</last_name>
    <role>Study Director</role>
    <affiliation>Aeras</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Aurum Institute - Klerksdorp</name>
      <address>
        <city>Klerksdorp</city>
        <zip>2571</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Aurum Institute - Rustenburg</name>
      <address>
        <city>Rustenburg</city>
        <zip>0300</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Aurum Institute - Tembisa</name>
      <address>
        <city>Tembisa</city>
        <zip>1632</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National Institute for Medical Research</name>
      <address>
        <city>Mwanza</city>
        <state>Isamilo Area</state>
        <country>Tanzania</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>South Africa</country>
    <country>Tanzania</country>
  </location_countries>
  <verification_date>April 2018</verification_date>
  <study_first_submitted>August 24, 2017</study_first_submitted>
  <study_first_submitted_qc>August 28, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 29, 2017</study_first_posted>
  <last_update_submitted>April 6, 2018</last_update_submitted>
  <last_update_submitted_qc>April 6, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">April 10, 2018</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>Tuberculosis</mesh_term>
    <mesh_term>Latent Tuberculosis</mesh_term>
  </condition_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/NCT03265977
org study id: A-043
nct id: NCT03265977
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This clinical trial will evaluate safety, immunogenicity, and efficacy (prevention of Mtb
      infection as measured by IGRA conversions) of H56:IC31 in remotely BCG vaccinated
      adolescents.
This clinical trial will evaluate safety, immunogenicity, and prevention of Mtb infection,
      (measured by IGRA conversion) of H56:IC31 in remotely BCG vaccinated adolescents. A TB
      vaccination strategy incorporating H56:IC31 in adolescents or young adults, if found to
      prevent Mtb infection, would likely have a major impact on TB disease, TB transmission, and
      control of the epidemic. If vaccination with H56:IC31 is shown to prevent infection with Mtb
      in this proof of concept study in adolescents, additional larger scale studies examining the
      impact on TB disease in more diverse populations would be warranted.

      Primary objectives

        -  To evaluate the safety profile of H56:IC31 compared to placebo in HIV-uninfected,
           remotely BCG vaccinated adolescents.

        -  To evaluate prevention of Mtb infection by H56:IC31 compared to placebo, as measured by
           rates of conversion using an ESAT-6 free IGRA.

      Secondary objectives

        -  To evaluate prevention of Mtb infection by H56:IC31 compared to placebo, as measured by
           rates of sustained conversion using an ESAT-6 free IGRA.

        -  To evaluate trends in ESAT-6 free IGRA prolonged/sustained conversions and late
           reversions (i.e., through more than 6 months post initial conversion) in ESAT-6 free
           IGRA converters.

        -  To investigate the immunogenicity of H56:IC31 in HIV-uninfected, remotely BCG vaccinated
           adolescents.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Participants will be enrolled in two cohorts. Within each cohort participants will be randomized in a 1:1 ratio to receive either H56:IC31 (5 ug H56/500 nmol IC31) or placebo intramuscularly (IM) on Days 0 and 56.
primary purpose: Prevention
masking: Triple (Participant, Care Provider, Investigator)
masking description: Random numbers generated by IWRS; Stratified by site. Syringes are masked with a translucent colored label, in order to maintain the study blind.
measure: Frequency and severity of adverse events
time frame: Day 0 through month 24
description: To evaluate the safety profile of H56:IC31 compared to placebo in HIV-uninfected, previously BCG vaccinated adolescents.
measure: ESAT-6 free IGRA conversion from a negative to positive test at any time point after Day 84 and through end of follow-up for the primary endpoint.
time frame: Day 84 through month 24
description: To evaluate prevention of Mtb infection by H56:IC31 compared to placebo, as measured by rates of conversion using an ESAT-6 free IGRA.
measure: Primary ESAT-6 free IGRA conversion from a negative to a positive test
time frame: Day 84 through month 24
description: Primary ESAT-6 free IGRA conversion from a negative to a positive test at any time point after Day 84 and through end of follow up for the primary endpoint, AND persisting without ESAT-6 free IGRA reversion from a positive to a negative test through 6 months after ESAT-6 free IGRA conversion.
measure: Primary ESAT-6 free IGRA conversion from a negative to a positive test
time frame: Day 84 through end of study (approximately 24 months)
description: Primary ESAT-6 free IGRA conversion from a negative to a positive test at any time point after randomization and through end of follow up for the primary endpoint, AND persisting without ESAT-6 free IGRA reversion from a positive to a negative test through 6 months after ESAT-6 free IGRA conversion.
measure: Initial ESAT-6 free IGRA reversion from a positive to a negative test at any time point after primary ESAT-6 free IGRA conversion through the end of follow up.
time frame: Day 84 through month 24
description: To evaluate trends in ESAT-6 free IGRA prolonged/sustained conversions and late reversions (i.e., through more than 6 months post initial conversion) in ESAT-6 free IGRA converters.
measure: Percentage of CD4+ and CD8+ T cells that express IFN-γ, TNF, and/or IL-2 alone or in combination in response to stimulation with peptide pools representing the entire amino acid sequence of the vaccine antigens.
time frame: Day 0 through month 24
description: Immunogenicity of H56:IC31 in HIV-uninfected, previously BCG vaccinated adolescents.
arm group label: H56:IC31
arm group type: Experimental
description: 5 ug H56/500 nmol IC31, 0.5 mL Intramuscular (IM), Days 0 and 56
arm group label: Placebo
arm group type: Placebo Comparator
description: Normal saline, 0.5 mL IM, Days 0 and 56
intervention type: Biological
intervention name: H56:IC31
description: The H56 antigen is a fusion protein created from 3 Mtb antigens: antigen 85B (Ag85B), ESAT-6, and Rv2660c.
arm group label: H56:IC31
intervention type: Other
intervention name: Placebo
description: Normal saline
arm group label: Placebo
criteria: 
gender: All
minimum age: 12 Years
maximum age: 17 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Dereck Tait, MD
role: Study Director
affiliation: Aeras
facility: 
facility: 
facility: 
facility: 
country: South Africa
country: Tanzania
responsible party type: Sponsor
mesh term: Infections
mesh term: Tuberculosis
mesh term: Latent Tuberculosis
sharing ipd: Undecided