<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/NCT03001986</url>
  </required_header>
  <id_info>
    <org_study_id>2016-012-03</org_study_id>
    <nct_id>NCT03001986</nct_id>
  </id_info>
  <brief_title>The Phase IVb of Inactivated Enterovirus 71 Vaccine (Human Diploid Cell, KMB-17) in Chinese Children</brief_title>
  <official_title>Effectiveness and Safety of Inactivated EV71 Vaccine (Human Diploid Cell) in 6-71 Months Children: an Open-label Controlled Phase Ⅳ Clinical Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cancer Institute and Hospital, Chinese Academy of Medical Sciences</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Hubei Provincial Center for Disease Control and Prevention</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Cancer Institute and Hospital, Chinese Academy of Medical Sciences</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Enterovirus 71 (EV71), a major pathogen causing hand-foot-and-mouth disease (HFMD) worldwide,&#xD;
      is a member of the Human Enterovirus species A, family Picornaviridae. Its infection&#xD;
      occasionally leads to severe diseases and death, with central nervous system (CNS) damage.&#xD;
&#xD;
      An inactivated EV71 vaccine (Human Diploid cell, KMB-17 Cell) has been finished phase I, II&#xD;
      and III clinical trials and licensed by CFDA in China at Dec. 3, 2015. Based on the results&#xD;
      of clinical trials, the protective efficacy of inactivated EV71 vaccine is 97% against HFMD&#xD;
      caused by EV71. The target population is determined to be susceptible children aged 6 to 71&#xD;
      months; this target population is well known as a major global population with strict&#xD;
      requirements for safety and efficacy of vaccines in implementing the World Health&#xD;
      Organization (WHO) Expanded Program on Immunization (EPI) . Thus, it is necessary and&#xD;
      significant to conduct a postmarketing phase IV trial in large populations for long-term&#xD;
      observation to evaluate the distinctive effectiveness and to identify potential safety issues&#xD;
      .&#xD;
&#xD;
      This study is an open-label and controlled postmarketing phase IV trial on children aged 6-71&#xD;
      months who resided in 3 districts of Xiangyang City, Hubei Province, China.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Primary Objective: To evaluate the effectiveness of EV71 vaccine after mass vaccination in a&#xD;
      large population (Chinese healthy children aged 6-71 months) for preventing against&#xD;
      EV71-associated hand, foot and mouth disease.&#xD;
&#xD;
      Secondary Objective: To evaluate the safety of EV71 vaccine after mass vaccination in a large&#xD;
      population (Chinese healthy children aged 6-71 months).&#xD;
&#xD;
      Participants: The children aged 6-71 months in the study area registered in August 2016 in&#xD;
      the Childhood Immunization Information Management System (CIIMS) in Hubei Province are&#xD;
      designated as study population. Of these children, 39189 will be recruited in the vaccine&#xD;
      group for receiving 2 doses of EV71 inactivated vaccine at an interval of 1 month. The&#xD;
      remaining children will be used as the control group.&#xD;
&#xD;
      Sampling size: The total sample size is primarily calculated based on the previous HFMD&#xD;
      monitoring data of the study sites from 2010 to 2015 by stratifying the data into 6 age&#xD;
      groups as follows: 6-11 months, 12-23 months, 24-35 months, 36-47 months, 48-59 months and&#xD;
      60-71 months, respectively. Prior to the identification of minimum annual HFMD incidences&#xD;
      caused by EV71 infection are 0.08%-6.05% (data not shown). Assuming a vaccine effectiveness&#xD;
      of 90% , power of 0.80 with a 0.05 significance level (two-tailed), and drop-out rate of 20%&#xD;
      , the sample size would be 39189 in the vaccine group.&#xD;
&#xD;
      Standard Operating Procedures:&#xD;
&#xD;
        1. Recruitment among the study population.&#xD;
&#xD;
        2. Recruit the study participants, and the children's guardians sign the informed consent.&#xD;
&#xD;
        3. The participants receive the 1st dose EV71 vaccine.&#xD;
&#xD;
        4. Observation for 30 minutes after vaccination in the vaccination clinic.&#xD;
&#xD;
        5. Follow up the enrolled participants by using contact card for recording any occurred AEs&#xD;
           of for a period of 30 days p.i. through home visits (in villages) or telephone visits&#xD;
           (in urban communities) within 30 days p.i. the first injection.&#xD;
&#xD;
        6. The participants receive the 2nd dose EV71 vaccine.&#xD;
&#xD;
        7. Observation for 30 minutes after vaccination in the vaccination clinic.&#xD;
&#xD;
        8. Follow up the enrolled participants by using contact card for recording any occurred AEs&#xD;
           of for a period of 30 days p.i. through home visits (in villages) or telephone visits&#xD;
           (in urban communities) within 30 days p.i. the second injection.&#xD;
&#xD;
        9. Twenty-eight days p.i.of the 2nd vaccination dose, conduct HFMD case surveillance on all&#xD;
           participants in the vaccine and control groups for a follow-up period of up to 14 months&#xD;
           through the database of Notifiable Infectious Diseases Network in Hubei, and detect EV71&#xD;
           in associated feces or anal swab specimens that are collected at hospitals or Community&#xD;
           Healthcare Service Centers by real-time PCR (RT-PCR).&#xD;
&#xD;
      Statistical Analysis Plan:&#xD;
&#xD;
      Primary statistical analysis will be to calculate the vaccine effectiveness against&#xD;
      EV71-associated HFMD, and to compare incidence density of EV71-associated HFMD between&#xD;
      vaccine group and control group.&#xD;
&#xD;
      Secondary analyses will be to calculate the vaccine effectiveness against EV71-associated&#xD;
      severe HFMD and EV71-associated hospitalized HFMD, and to describe adverse events in the&#xD;
      vaccine recipients.&#xD;
&#xD;
      Quality Assurance Plan:&#xD;
&#xD;
        1. Training Investigators: Administrative and technical personnel at all levels in study&#xD;
           areas are required to participate in training on the study objectives, enrollment&#xD;
           procedures, follow-up requirement, data collection, quality control measures, sample&#xD;
           handling and transport, and all other operations involved.&#xD;
&#xD;
        2. Supervision and Monitoring: Institute of Medical Biology, Chinese Academy of Medical&#xD;
           Science (IMBCAMS) and the Hubei province Center for Control and Prevention (Hubei CDC )&#xD;
           will supervise and monitor vaccination clinic during the implementation period according&#xD;
           to the progress of study; and the Xiangyang City Center for Control and Prevention will&#xD;
           supervise and monitor each vaccination clinic on selected appointment days. The focus of&#xD;
           supervision and monitoring will be to observe whether the vaccination clinics strictly&#xD;
           follow protocols and procedures and any problems found can be quickly resolved with&#xD;
           timely feedback. Any serious and consistent problems will be reported to the higher&#xD;
           level, so that corrections can be made timely.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 2016</start_date>
  <completion_date type="Actual">December 2017</completion_date>
  <primary_completion_date type="Actual">December 2017</primary_completion_date>
  <phase>Phase 4</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>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The effectiveness of inactivated EV71 vaccine in preventing hand-foot-and-mouth disease (HFMD) caused by Enterovirus 71 (EV71) in large scale population of Chinese children (from 6 to 71 months old) in Hubei Province, China.</measure>
    <time_frame>Up to 14 months from twenty-eight days p.i.of the 2nd vaccination dose</time_frame>
    <description>The effectiveness of inactivated EV71 vaccine and 95% confidence intervals were calculated on the basis of the observed difference of incidence between the children (from 6 to 71 months old) who were vaccinated and those who were not vaccinated.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of treatment adverse events</measure>
    <time_frame>Within 30 days postinoculation each dose</time_frame>
    <description>The adverse events were observed and recorded within 30 minutes post immunization (p.i.), within 30 days after the 1st injection, as well as after the 2nd injection.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">40724</enrollment>
  <condition>Hand, Foot and Mouth Disease (HFMD)</condition>
  <arm_group>
    <arm_group_label>vaccine (3.0 EU)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>healthy children (6-71 months old) have been injected by inactivated EV71 vaccine (KMB-17) of 3.0 EU (neutralization antibodies titer unit; 100 U in phase III clinical trials, or 320 EU (Elisa assay unit) in phase I and II clinical trials)</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>inactivated EV71 vaccine (KMB-17 cells)</intervention_name>
    <description>Receiving 2 doses of the EV71 inactivated vaccine at an interval of 1 month.</description>
    <arm_group_label>vaccine (3.0 EU)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy subjects (6-71 months old children)&#xD;
&#xD;
          -  The subjects' legal guardian voluntarily participate in the study and signed Informed&#xD;
             Consent Form&#xD;
&#xD;
          -  The subjects' legal guardian with the ability and objective to comply with the&#xD;
             requirements of the protocol&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Allergy to a vaccine , any ingredient of vaccine or substance used in the preparation&#xD;
             process including excipients, formaldehyde, and kanamycin sulfate.&#xD;
&#xD;
          -  Fever, acute illness&#xD;
&#xD;
          -  Severe chronic disease, allergic diathesis&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Months</minimum_age>
    <maximum_age>71 Months</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Xuhua Guan, M.S.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hubei Province Center for Diseases Control and Prevention</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hubei Province Center for Diseases Control and Prevention</name>
      <address>
        <city>Wuhan</city>
        <state>Hubei</state>
        <zip>430079</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>September 17, 2016</study_first_submitted>
  <study_first_submitted_qc>December 20, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 23, 2016</study_first_posted>
  <last_update_submitted>April 26, 2019</last_update_submitted>
  <last_update_submitted_qc>April 26, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">April 30, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Cancer Institute and Hospital, Chinese Academy of Medical Sciences</investigator_affiliation>
    <investigator_full_name>Qihan Li</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>effectiveness</keyword>
  <keyword>safety</keyword>
  <keyword>hand, foot and mouth disease (HFMD)</keyword>
  <keyword>Enterovirus A, Human</keyword>
  <keyword>vaccine</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Foot-and-Mouth Disease</mesh_term>
    <mesh_term>Hand, Foot and Mouth Disease</mesh_term>
    <mesh_term>Mouth Diseases</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Participants do not agree to share individual data.</ipd_description>
  </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/NCT03001986
org study id: 2016-012-03
nct id: NCT03001986
lead sponsor: 
collaborator: 
has dmc: No
Enterovirus 71 (EV71), a major pathogen causing hand-foot-and-mouth disease (HFMD) worldwide,
      is a member of the Human Enterovirus species A, family Picornaviridae. Its infection
      occasionally leads to severe diseases and death, with central nervous system (CNS) damage.

      An inactivated EV71 vaccine (Human Diploid cell, KMB-17 Cell) has been finished phase I, II
      and III clinical trials and licensed by CFDA in China at Dec. 3, 2015. Based on the results
      of clinical trials, the protective efficacy of inactivated EV71 vaccine is 97% against HFMD
      caused by EV71. The target population is determined to be susceptible children aged 6 to 71
      months; this target population is well known as a major global population with strict
      requirements for safety and efficacy of vaccines in implementing the World Health
      Organization (WHO) Expanded Program on Immunization (EPI) . Thus, it is necessary and
      significant to conduct a postmarketing phase IV trial in large populations for long-term
      observation to evaluate the distinctive effectiveness and to identify potential safety issues
      .

      This study is an open-label and controlled postmarketing phase IV trial on children aged 6-71
      months who resided in 3 districts of Xiangyang City, Hubei Province, China.
Primary Objective: To evaluate the effectiveness of EV71 vaccine after mass vaccination in a
      large population (Chinese healthy children aged 6-71 months) for preventing against
      EV71-associated hand, foot and mouth disease.

      Secondary Objective: To evaluate the safety of EV71 vaccine after mass vaccination in a large
      population (Chinese healthy children aged 6-71 months).

      Participants: The children aged 6-71 months in the study area registered in August 2016 in
      the Childhood Immunization Information Management System (CIIMS) in Hubei Province are
      designated as study population. Of these children, 39189 will be recruited in the vaccine
      group for receiving 2 doses of EV71 inactivated vaccine at an interval of 1 month. The
      remaining children will be used as the control group.

      Sampling size: The total sample size is primarily calculated based on the previous HFMD
      monitoring data of the study sites from 2010 to 2015 by stratifying the data into 6 age
      groups as follows: 6-11 months, 12-23 months, 24-35 months, 36-47 months, 48-59 months and
      60-71 months, respectively. Prior to the identification of minimum annual HFMD incidences
      caused by EV71 infection are 0.08%-6.05% (data not shown). Assuming a vaccine effectiveness
      of 90% , power of 0.80 with a 0.05 significance level (two-tailed), and drop-out rate of 20%
      , the sample size would be 39189 in the vaccine group.

      Standard Operating Procedures:

        1. Recruitment among the study population.

        2. Recruit the study participants, and the children's guardians sign the informed consent.

        3. The participants receive the 1st dose EV71 vaccine.

        4. Observation for 30 minutes after vaccination in the vaccination clinic.

        5. Follow up the enrolled participants by using contact card for recording any occurred AEs
           of for a period of 30 days p.i. through home visits (in villages) or telephone visits
           (in urban communities) within 30 days p.i. the first injection.

        6. The participants receive the 2nd dose EV71 vaccine.

        7. Observation for 30 minutes after vaccination in the vaccination clinic.

        8. Follow up the enrolled participants by using contact card for recording any occurred AEs
           of for a period of 30 days p.i. through home visits (in villages) or telephone visits
           (in urban communities) within 30 days p.i. the second injection.

        9. Twenty-eight days p.i.of the 2nd vaccination dose, conduct HFMD case surveillance on all
           participants in the vaccine and control groups for a follow-up period of up to 14 months
           through the database of Notifiable Infectious Diseases Network in Hubei, and detect EV71
           in associated feces or anal swab specimens that are collected at hospitals or Community
           Healthcare Service Centers by real-time PCR (RT-PCR).

      Statistical Analysis Plan:

      Primary statistical analysis will be to calculate the vaccine effectiveness against
      EV71-associated HFMD, and to compare incidence density of EV71-associated HFMD between
      vaccine group and control group.

      Secondary analyses will be to calculate the vaccine effectiveness against EV71-associated
      severe HFMD and EV71-associated hospitalized HFMD, and to describe adverse events in the
      vaccine recipients.

      Quality Assurance Plan:

        1. Training Investigators: Administrative and technical personnel at all levels in study
           areas are required to participate in training on the study objectives, enrollment
           procedures, follow-up requirement, data collection, quality control measures, sample
           handling and transport, and all other operations involved.

        2. Supervision and Monitoring: Institute of Medical Biology, Chinese Academy of Medical
           Science (IMBCAMS) and the Hubei province Center for Control and Prevention (Hubei CDC )
           will supervise and monitor vaccination clinic during the implementation period according
           to the progress of study; and the Xiangyang City Center for Control and Prevention will
           supervise and monitor each vaccination clinic on selected appointment days. The focus of
           supervision and monitoring will be to observe whether the vaccination clinics strictly
           follow protocols and procedures and any problems found can be quickly resolved with
           timely feedback. Any serious and consistent problems will be reported to the higher
           level, so that corrections can be made timely.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: The effectiveness of inactivated EV71 vaccine in preventing hand-foot-and-mouth disease (HFMD) caused by Enterovirus 71 (EV71) in large scale population of Chinese children (from 6 to 71 months old) in Hubei Province, China.
time frame: Up to 14 months from twenty-eight days p.i.of the 2nd vaccination dose
description: The effectiveness of inactivated EV71 vaccine and 95% confidence intervals were calculated on the basis of the observed difference of incidence between the children (from 6 to 71 months old) who were vaccinated and those who were not vaccinated.
measure: Incidence of treatment adverse events
time frame: Within 30 days postinoculation each dose
description: The adverse events were observed and recorded within 30 minutes post immunization (p.i.), within 30 days after the 1st injection, as well as after the 2nd injection.
arm group label: vaccine (3.0 EU)
arm group type: Experimental
description: healthy children (6-71 months old) have been injected by inactivated EV71 vaccine (KMB-17) of 3.0 EU (neutralization antibodies titer unit; 100 U in phase III clinical trials, or 320 EU (Elisa assay unit) in phase I and II clinical trials)
intervention type: Biological
intervention name: inactivated EV71 vaccine (KMB-17 cells)
description: Receiving 2 doses of the EV71 inactivated vaccine at an interval of 1 month.
arm group label: vaccine (3.0 EU)
criteria: 
gender: All
minimum age: 6 Months
maximum age: 71 Months
healthy volunteers: Accepts Healthy Volunteers
last name: Xuhua Guan, M.S.
role: Principal Investigator
affiliation: Hubei Province Center for Diseases Control and Prevention
facility: 
country: China
responsible party type: Principal Investigator
investigator affiliation: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
investigator full name: Qihan Li
investigator title: Professor
mesh term: Foot-and-Mouth Disease
mesh term: Hand, Foot and Mouth Disease
mesh term: Mouth Diseases
sharing ipd: No
ipd description: Participants do not agree to share individual data.