<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/NCT03299426</url>
  </required_header>
  <id_info>
    <org_study_id>HP-00076625</org_study_id>
    <nct_id>NCT03299426</nct_id>
  </id_info>
  <brief_title>Clinical Efficacy of Typhoid Conjugate Vaccine (Vi-TCV) Among Children Age 9 Months Through 12 Years in Blantyre, Malawi</brief_title>
  <official_title>A Phase III Randomized, Double-Blind, Controlled Trial of the Clinical Efficacy of Typhoid Conjugate Vaccine (Vi-TCV) Among Children Age 9 Months Through 12 Years in Blantyre, Malawi</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Maryland, Baltimore</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bill and Melinda Gates Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Malawi-Liverpool-Wellcome Trust Clinical Research Programme</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University College, London</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Malawi</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Maryland, Baltimore</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will evaluate the efficacy of a Typhoid conjugate vaccine (Vi-TCV) in Malawi,&#xD;
      Africa among children age 9 months through 12 years. Participants will be randomized in a 1:1&#xD;
      ration to receive the study vaccine or the control vaccine (meningococcal group A conjugate&#xD;
      vaccine - MCV-A).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study is a double-blind, individually randomized, controlled, clinical efficacy trial&#xD;
      with two vaccine groups: Vi-TCV (Typhoid conjugate) and MCV-A (meningococcal group A&#xD;
      conjugate). This study will take place in Blantyre, Malawi, Africa. Participants (up to&#xD;
      30,000) will be randomized in a 1:1 ratio. Children 9 months through 12 years of age in the&#xD;
      Blantyre area who meet the inclusion criteria will be eligible for enrollment.&#xD;
&#xD;
      Participants will be unaware of which study vaccine, Vi-TCV or MCV-A, is received. A subset&#xD;
      of 600 children will have study visits on days 3, 7, 28 and 180 post-vaccination to assess&#xD;
      select solicited events, unsolicited events, and all serious adverse events. Serious Adverse&#xD;
      Events (SAEs) in all participants will be monitored through the end of the trial.&#xD;
&#xD;
      For the evaluation of efficacy, passive surveillance will be conducted for up to 36 months to&#xD;
      identify cases among vaccinated subjects. Children who meet the protocol-defined specimen&#xD;
      collection criteria will have a blood culture collected. Additional information will be&#xD;
      collected from any child who has a blood culture obtained. This will include information&#xD;
      about the signs and symptoms of the illness and treatment given. Likewise, any child with&#xD;
      blood culture-confirmed typhoid fever will have follow-up until the illness resolves.&#xD;
      Additional information on the illness, treatment and complications will be recorded. Vaccine&#xD;
      efficacy will be evaluated when the pre-specified number of cases is reached after a minimum&#xD;
      of two years of follow-up on each participant.&#xD;
&#xD;
      A subset of 600 children (200 in each of three age groups: 9-11 months, 1-5 years, and 6-12&#xD;
      years) will be included in an additional Vaccine Immunogenicity and Reactogenicity Sub-study.&#xD;
      More stringent exclusion criteria will apply for this subset. The purpose of this detailed&#xD;
      evaluation is to assess the reactogenicity of the vaccine and the immune responses to Vi-TCV.&#xD;
      Serum specimens will be collected on day 0 (before vaccination) and on post-vaccination days&#xD;
      28 and 730 from all children included in the sub-study. For the children in the 9-11 month&#xD;
      group, Vi-TCV or MCV-A will be administered with measles-containing vaccine, as per Malawi&#xD;
      Expanded Programme on Immunization (EPI) schedule. These 9-11-month-old children will have&#xD;
      antibody to measles assessed on days 0 and 28. All children in the sub-study will have visits&#xD;
      at days 4 and 7 following vaccination for solicitation of local and systemic adverse events.&#xD;
      Serious and non-serious adverse events will be assessed at days 28 and 180.&#xD;
&#xD;
      An additional subset of -up to 225 HIV-exposed-but-uninfected and up to 100 HIV-unexposed&#xD;
      children ages 9-11 months will be included in an additional HIV-exposed Vaccine&#xD;
      Immunogenicity and Reactogenicity Substudy. The purpose of this detailed evaluation is to&#xD;
      assess the reactogenicity of the vaccine and the immune responses to one or two doses of&#xD;
      Vi-TCV in HIV-exposed children. Up to 225 HIV-exposed children in this substudy will be&#xD;
      randomized 1:1:1 to receive either TCV at 9-11 months and TCV at 15 months (Group 1), TCV at&#xD;
      9-11 months only (Group 2), or TCV at 15 months only (Group 3). A separate group of about 100&#xD;
      HIV-unexposed children will serve as controls and receive TCV at 9-11 months and TCV at 15&#xD;
      months (Group 4). Serum specimens will be collected on day 0 (before vaccination) and on 28&#xD;
      days after each vaccination from all children included in the sub-study. For this substudy,&#xD;
      Vi-TCV will be administered with measles-rubella-containing vaccine #1 at 9-11 months and/or&#xD;
      #2 at 15 months, as per Malawi EPI schedule. These 9-11-month-old children will have antibody&#xD;
      to typhoid, measles, and rubella assessed on day 0 and 28 days after each vaccination. All&#xD;
      children in the sub-study will be assessed at 7 days after each vaccination for solicitation&#xD;
      of local and systemic adverse events. Serious and non-serious adverse events will be assessed&#xD;
      up to the last study visit for HIV-exposed substudy participants.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">February 21, 2018</start_date>
  <completion_date type="Anticipated">October 30, 2025</completion_date>
  <primary_completion_date type="Anticipated">October 30, 2024</primary_completion_date>
  <phase>Phase 3</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>Prevention</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Efficacy of Vi-TCV</measure>
    <time_frame>Up to 36 months</time_frame>
    <description>The primary outcome of interest is the incidence of blood culture-positive typhoid fever among Vi-TCV and MCV-A vaccine recipients in the study population during the entire post-vaccination surveillance period. Vaccine efficacy will be calculated as one minus the relative rate of symptomatic typhoid fever in the Vi-TCV group compared to that in the MCV-A group.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety of Vi-TCV</measure>
    <time_frame>6 months</time_frame>
    <description>The safety profile of Vi-TCV will be measured by comparing the proportions of participants experiencing solicited and unsolicited local and systemic reactions between children receiving Vi-TCV as compared to children receiving MCV-A according to the following three categories:&#xD;
The proportion of participants who develop adverse events detected in the first 30 minutes after vaccination and for 7 days after vaccination.&#xD;
The proportion of participants who experience serious adverse events within 6 months of vaccination in a subset of participants.&#xD;
The proportion of participants who experience other non-serious adverse events up to 28 days following vaccination, in a subset of participants.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunogenicity of Vi-TCV</measure>
    <time_frame>28 days</time_frame>
    <description>The immunogenicity of Vi-TCV in a subset of 600 participants measured by ELISA for anti-Vi percent seroconversion and GMTs before and at day 28 after vaccination.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of typhoid fever cases prevented Vi-TCV</measure>
    <time_frame>Up to 36 months</time_frame>
    <description>The number of blood culture-confirmed cases of typhoid fever prevented by Vi-TCV during the study period measured by comparing the incidence of blood culture-confirmed typhoid fever in participants receiving Vi-TCV compared to those receiving MCV-A.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">30000</enrollment>
  <condition>Typhoid</condition>
  <arm_group>
    <arm_group_label>Vi-Typhoid Conjugate Vaccine (Vi-TCV)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Children will receive a single 0.5-ml dose of Vi-TCV administered by the intramuscular route.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Meningococcal A Conjugate Vaccine (MCV-A)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Children will receive a single dose of MCV-A administered by the intramuscular route. Children 9-11 months will receive a 5µg/0.5ml dose. Children 12 months and older will receive a 10µg/0.5 ml dose.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Vi-Typhoid Conjugate Vaccine (Vi-TCV)</intervention_name>
    <description>Single 0.5-ml intramuscular injection</description>
    <arm_group_label>Vi-Typhoid Conjugate Vaccine (Vi-TCV)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Meningococcal A Conjugate Vaccine (MCV-A)</intervention_name>
    <description>Single intramuscular injection. Children 9-11 months will receive a 5µg/0.5ml dose. Children 12 months and older will receive a 10µg/0.5 ml dose.</description>
    <arm_group_label>Meningococcal A Conjugate Vaccine (MCV-A)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy male or female child between the ages of 9 months and 12 years/364 days at the&#xD;
             time of study vaccination.&#xD;
&#xD;
          -  A child whose parent or guardian resides primarily within the Ndirande or Zingwangwa&#xD;
             study areas at the time of study vaccinations and who intends to be present in the&#xD;
             area for the duration of the trial.&#xD;
&#xD;
          -  A child whose parent or guardian has voluntarily given informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of documented hypersensitivity to any component of the vaccine&#xD;
&#xD;
          -  Prior receipt of any typhoid vaccine in the past 3 years&#xD;
&#xD;
          -  History of severe allergic reaction with generalized urticarial, angioedema, or&#xD;
             anaphylaxis&#xD;
&#xD;
          -  Any condition determined by the investigator to be likely to interfere with evaluation&#xD;
             of the vaccine or to be a significant potential health risk to the child or make it&#xD;
             unlikely that the child would complete the study.&#xD;
&#xD;
        Temporary Exclusion Criteria:&#xD;
&#xD;
        The following will be considered temporary contraindications to enrollment and vaccination.&#xD;
        If these apply, the participant will be temporarily excluded for vaccination until 48 hours&#xD;
        has passed. A re-assessment will be needed to ensure these temporary exclusion criteria no&#xD;
        longer exist.&#xD;
&#xD;
          -  Reported fever within 24 hours prior to vaccination&#xD;
&#xD;
          -  Use of anti-pyretics within 4 hours prior to vaccination&#xD;
&#xD;
        An additional temporary exclusion criteria will be:&#xD;
&#xD;
        - Receipt of measles vaccine in the one month prior to enrollment, as determined by&#xD;
        parental history or vaccination card.&#xD;
&#xD;
        Additional Exclusion Criteria for Safety and Immunogenicity Substudy:&#xD;
&#xD;
        In addition to the exclusion criteria of the efficacy study, participants enrolled in the&#xD;
        immunogenicity and reactogenicity substudy may not have, or have had, any:&#xD;
&#xD;
          -  Known history of diabetes, tuberculosis, cancer, chronic kidney, heart, or liver&#xD;
             disease, progressive neurological disorders, poorly controlled seizures, or terminal&#xD;
             illness&#xD;
&#xD;
          -  Severe malnutrition as determined by MUAC&lt; 12.5 cm for children younger than 5 years;&#xD;
&#xD;
          -  Receipt of any other investigational intervention in the last 6 months or anticipated&#xD;
             during the course of the study.&#xD;
&#xD;
          -  Receipt of blood products in the last 6 months.&#xD;
&#xD;
          -  Known HIV-infection or exposure or other immunosuppressive conditions.&#xD;
&#xD;
          -  Receipt of systemic immunosuppressant or systemic corticosteroids.&#xD;
&#xD;
          -  Receipt of any measles-containing vaccine for children younger than 1 year of age&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>9 Months</minimum_age>
    <maximum_age>12 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kathleen Neuzil, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Maryland School of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Malawi Liverpool Wellcome Trust Clinical Research Programme, Queen Elizabeth Central Hospital College of Medicine</name>
      <address>
        <city>Blantyre</city>
        <zip>P.O. Box 30096</zip>
        <country>Malawi</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Malawi</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>September 27, 2017</study_first_submitted>
  <study_first_submitted_qc>September 27, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 3, 2017</study_first_posted>
  <last_update_submitted>February 6, 2023</last_update_submitted>
  <last_update_submitted_qc>February 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 8, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Maryland, Baltimore</investigator_affiliation>
    <investigator_full_name>Kathleen Neuzil</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Typhoid</keyword>
  <keyword>Typhoid in Malawi</keyword>
  <keyword>Typhoid Vaccine</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Typhoid Fever</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vaccines</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/NCT03299426
org study id: HP-00076625
nct id: NCT03299426
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
This study will evaluate the efficacy of a Typhoid conjugate vaccine (Vi-TCV) in Malawi,
      Africa among children age 9 months through 12 years. Participants will be randomized in a 1:1
      ration to receive the study vaccine or the control vaccine (meningococcal group A conjugate
      vaccine - MCV-A).
This study is a double-blind, individually randomized, controlled, clinical efficacy trial
      with two vaccine groups: Vi-TCV (Typhoid conjugate) and MCV-A (meningococcal group A
      conjugate). This study will take place in Blantyre, Malawi, Africa. Participants (up to
      30,000) will be randomized in a 1:1 ratio. Children 9 months through 12 years of age in the
      Blantyre area who meet the inclusion criteria will be eligible for enrollment.

      Participants will be unaware of which study vaccine, Vi-TCV or MCV-A, is received. A subset
      of 600 children will have study visits on days 3, 7, 28 and 180 post-vaccination to assess
      select solicited events, unsolicited events, and all serious adverse events. Serious Adverse
      Events (SAEs) in all participants will be monitored through the end of the trial.

      For the evaluation of efficacy, passive surveillance will be conducted for up to 36 months to
      identify cases among vaccinated subjects. Children who meet the protocol-defined specimen
      collection criteria will have a blood culture collected. Additional information will be
      collected from any child who has a blood culture obtained. This will include information
      about the signs and symptoms of the illness and treatment given. Likewise, any child with
      blood culture-confirmed typhoid fever will have follow-up until the illness resolves.
      Additional information on the illness, treatment and complications will be recorded. Vaccine
      efficacy will be evaluated when the pre-specified number of cases is reached after a minimum
      of two years of follow-up on each participant.

      A subset of 600 children (200 in each of three age groups: 9-11 months, 1-5 years, and 6-12
      years) will be included in an additional Vaccine Immunogenicity and Reactogenicity Sub-study.
      More stringent exclusion criteria will apply for this subset. The purpose of this detailed
      evaluation is to assess the reactogenicity of the vaccine and the immune responses to Vi-TCV.
      Serum specimens will be collected on day 0 (before vaccination) and on post-vaccination days
      28 and 730 from all children included in the sub-study. For the children in the 9-11 month
      group, Vi-TCV or MCV-A will be administered with measles-containing vaccine, as per Malawi
      Expanded Programme on Immunization (EPI) schedule. These 9-11-month-old children will have
      antibody to measles assessed on days 0 and 28. All children in the sub-study will have visits
      at days 4 and 7 following vaccination for solicitation of local and systemic adverse events.
      Serious and non-serious adverse events will be assessed at days 28 and 180.

      An additional subset of -up to 225 HIV-exposed-but-uninfected and up to 100 HIV-unexposed
      children ages 9-11 months will be included in an additional HIV-exposed Vaccine
      Immunogenicity and Reactogenicity Substudy. The purpose of this detailed evaluation is to
      assess the reactogenicity of the vaccine and the immune responses to one or two doses of
      Vi-TCV in HIV-exposed children. Up to 225 HIV-exposed children in this substudy will be
      randomized 1:1:1 to receive either TCV at 9-11 months and TCV at 15 months (Group 1), TCV at
      9-11 months only (Group 2), or TCV at 15 months only (Group 3). A separate group of about 100
      HIV-unexposed children will serve as controls and receive TCV at 9-11 months and TCV at 15
      months (Group 4). Serum specimens will be collected on day 0 (before vaccination) and on 28
      days after each vaccination from all children included in the sub-study. For this substudy,
      Vi-TCV will be administered with measles-rubella-containing vaccine #1 at 9-11 months and/or
      #2 at 15 months, as per Malawi EPI schedule. These 9-11-month-old children will have antibody
      to typhoid, measles, and rubella assessed on day 0 and 28 days after each vaccination. All
      children in the sub-study will be assessed at 7 days after each vaccination for solicitation
      of local and systemic adverse events. Serious and non-serious adverse events will be assessed
      up to the last study visit for HIV-exposed substudy participants.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Efficacy of Vi-TCV
time frame: Up to 36 months
description: The primary outcome of interest is the incidence of blood culture-positive typhoid fever among Vi-TCV and MCV-A vaccine recipients in the study population during the entire post-vaccination surveillance period. Vaccine efficacy will be calculated as one minus the relative rate of symptomatic typhoid fever in the Vi-TCV group compared to that in the MCV-A group.
measure: Safety of Vi-TCV
time frame: 6 months
description: The safety profile of Vi-TCV will be measured by comparing the proportions of participants experiencing solicited and unsolicited local and systemic reactions between children receiving Vi-TCV as compared to children receiving MCV-A according to the following three categories:
The proportion of participants who develop adverse events detected in the first 30 minutes after vaccination and for 7 days after vaccination.
The proportion of participants who experience serious adverse events within 6 months of vaccination in a subset of participants.
The proportion of participants who experience other non-serious adverse events up to 28 days following vaccination, in a subset of participants.
measure: Immunogenicity of Vi-TCV
time frame: 28 days
description: The immunogenicity of Vi-TCV in a subset of 600 participants measured by ELISA for anti-Vi percent seroconversion and GMTs before and at day 28 after vaccination.
measure: Number of typhoid fever cases prevented Vi-TCV
time frame: Up to 36 months
description: The number of blood culture-confirmed cases of typhoid fever prevented by Vi-TCV during the study period measured by comparing the incidence of blood culture-confirmed typhoid fever in participants receiving Vi-TCV compared to those receiving MCV-A.
arm group label: Vi-Typhoid Conjugate Vaccine (Vi-TCV)
arm group type: Experimental
description: Children will receive a single 0.5-ml dose of Vi-TCV administered by the intramuscular route.
arm group label: Meningococcal A Conjugate Vaccine (MCV-A)
arm group type: Active Comparator
description: Children will receive a single dose of MCV-A administered by the intramuscular route. Children 9-11 months will receive a 5µg/0.5ml dose. Children 12 months and older will receive a 10µg/0.5 ml dose.
intervention type: Biological
intervention name: Vi-Typhoid Conjugate Vaccine (Vi-TCV)
description: Single 0.5-ml intramuscular injection
arm group label: Vi-Typhoid Conjugate Vaccine (Vi-TCV)
intervention type: Biological
intervention name: Meningococcal A Conjugate Vaccine (MCV-A)
description: Single intramuscular injection. Children 9-11 months will receive a 5µg/0.5ml dose. Children 12 months and older will receive a 10µg/0.5 ml dose.
arm group label: Meningococcal A Conjugate Vaccine (MCV-A)
criteria: 
gender: All
minimum age: 9 Months
maximum age: 12 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Kathleen Neuzil, MD
role: Principal Investigator
affiliation: University of Maryland School of Medicine
facility: 
country: Malawi
responsible party type: Principal Investigator
investigator affiliation: University of Maryland, Baltimore
investigator full name: Kathleen Neuzil
investigator title: Professor
mesh term: Typhoid Fever
mesh term: Vaccines