<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/NCT04467541</url>
  </required_header>
  <id_info>
    <org_study_id>PR-19055</org_study_id>
    <nct_id>NCT04467541</nct_id>
  </id_info>
  <brief_title>Safety &amp; Immunogenicity of Enterovirus Type 71 Vaccine in Healthy Adults and Children 6-71months</brief_title>
  <official_title>A Randomized, Open, Phase I/II to Evaluate the Inactivated EV 71 Vaccine Safety in Healthy Adults Followed by Safety and Immunogenicity Administered in 2 Consecutive Doses, 1 Month Apart Among Child Aged 6 to 71 Months.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>International Centre for Diarrhoeal Disease Research, Bangladesh</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>International Centre for Diarrhoeal Disease Research, Bangladesh</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>
      1. Burden: Hand-foot-and-mouth disease (HFMD) characterized by skin rash in extremities,&#xD;
           mouth ulcer and fever among &lt;5 years children.Primarily caused by Enterovirus-&#xD;
           predominantly human Enterovirus (EV) 71 and Coxsackie virus (CoxA). Several large&#xD;
           epidemics have been reported worldwide.Large Asia-Pacific epidemic-in China in 2008,&#xD;
           approximately 490,000 infections and 126 deaths of children. EV71 contributes severe and&#xD;
           fatal cases e.g. encephalitis.A recent outbreak of HFMD in Bhubaneswar, Odisha in India&#xD;
           indicates there is a chance of HFMD outbreaks in Bangladesh. However there is not much&#xD;
           report of HFMD from Bangladesh.&#xD;
&#xD;
        2. Knowledge gap: EV71 is most commonly transmitted via close person-to-person contact.&#xD;
           Since there is no known effective treatment for HFMD and as the causative virus is&#xD;
           highly contagious, hand washing is the best defense for prevention. However,&#xD;
           asymptomatic or mild nature of the infection leads to ineffectiveness of public health&#xD;
           interventions like hand washing. Thus the symptomatic management remains the mainstay of&#xD;
           treatment strategy for HFMD as of now. EV71 vaccine, an inactivated vaccine, developed&#xD;
           by Sinovac Biotech Ltd has shown satisfactory safety and effectiveness through Phase III&#xD;
           trials conducted in various regions of mainland China, This new vaccine has the&#xD;
           potential to significantly reduce suffering and death from EV71 disease in China.&#xD;
           However, it is not assessed on Bangladeshi child.&#xD;
&#xD;
        3. Relevance: Due to the absence of effective public health strategy and proper treatment,&#xD;
           the development of an effective vaccine may be the best way to control EV71 infection.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      General objective:&#xD;
&#xD;
        1. To evaluate the safety of EV71 vaccine in adults and in children age 6-71 months&#xD;
&#xD;
        2. To evaluate the immunogenicity of the vaccine in children by assessing the&#xD;
           neutralization antibody levels before immunization; then 7, 15, 30 days after the first&#xD;
           inoculation; and also 7, 15, 30 days after the second inoculation.&#xD;
&#xD;
        3. To assess the incidence rate of adverse reactions/events&#xD;
&#xD;
      Specific objective: To find out:&#xD;
&#xD;
        1. Seroconversion rate of neutralization antibody on the day 30 after the whole-range&#xD;
           immunization (i.e. after 2nd dose of vaccination);&#xD;
&#xD;
        2. Positive rate and Geometric Mean Titer of neutralization antibody on the day 30 after&#xD;
           the whole-range immunization;&#xD;
&#xD;
        3. Seroconversion rate, positive rate and Geometric Mean Titer of serum neutralization&#xD;
           antibody on the day 7, day 15, day 30 after the first inoculation;&#xD;
&#xD;
        4. Seroconversion rate,positive rate and Geometric Mean Titer of serum neutralization&#xD;
           antibody on the day 7, day 15 after the second inoculation;&#xD;
&#xD;
        5. The incidence rate of adverse reactions &amp; serious adverse events during the observation&#xD;
           period of safety;&#xD;
&#xD;
        6. The incidence rate of adverse reactions 0-30 days after each inoculation of vaccine;&#xD;
&#xD;
        7. The incidence rate of adverse events 0-7 days after each inoculation of vaccine;&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 24, 2019</start_date>
  <completion_date type="Actual">January 31, 2020</completion_date>
  <primary_completion_date type="Actual">January 31, 2020</primary_completion_date>
  <phase>Phase 1/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>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Neutralizing Antibody responses for evaluation of enterovirus 71( EV71) vaccines</measure>
    <time_frame>before immunization, 7, 15, 30 days after the first inoculation, 7, 15, 30 days after the second inoculation</time_frame>
    <description>Testing the neutralization antibody levels before immunization, 7, 15, 30 days after Ist inoculation, 7, 15, 30 days after the 2nd inoculation, calculate the positive seroconversion rate, the positive rate and geometric mean titre of neutralization antibody.&#xD;
Vaccine recipients will have greater increase in neutralization antibody titers (NT) after the first dose, without a further increase in NT after the second dose. The seroconversion rate will be increased after Ist &amp; second inoculation&#xD;
Detection Method of the Anti-EV71 Neutralizing Antibody&#xD;
Sample collection and processing&#xD;
Serum will be examined to determine the potency of the neutralizing antibody&#xD;
Treatment of the serum to be examined&#xD;
Dilution of the serum to be examined and virus used for neutralization:&#xD;
Serum and virus neutralizing and virus culture&#xD;
Observation of the cytopathic change and judgment results</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety Outcome</measure>
    <time_frame>After Ist vacctination (0 day) &amp; 30 days after 2nd vaccination</time_frame>
    <description>Solicited AE's (Local) e.g. Tenderness, Indurations, Redness, swelling Rash (Injection site), Pruritus with Grading &amp; Solicited AE's (Systemic) e.g. Allergic Reaction, Fatigue, Asthenia, Dysphoria, Loss of Appetite Nausea, Vomiting, Diarrhea Fever (Axillary Temp)with Grading will be assessed.&#xD;
If any solicited or unsolicited AE's following vaccination in this study and will record adverse events at home in diary card.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">430</enrollment>
  <condition>Hand Foot &amp; Mouth Disease</condition>
  <arm_group>
    <arm_group_label>Inactivated enterovirus type 71 vaccine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Inactivated enterovirus type 71 vaccine safety in healthy adults followed by safety and immunogenicity administered in two consecutive doses, one-month apart among children aged 6 to 71 months</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Inactivated Enterovirus Type 71 (EV71) Vaccine (Vero Cell)</intervention_name>
    <description>Inactivated Enterovirus Type 71 (EV71) Vaccine safety in healthy adults followed by safety and immunogenicity administered in two consecutive doses, one-month apart among children aged 6 to 71 months</description>
    <arm_group_label>Inactivated enterovirus type 71 vaccine</arm_group_label>
    <other_name>Inlive</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Bangladeshi healthy adults 18-45yrs and children aged 6-71 months on the day of&#xD;
             screening;&#xD;
&#xD;
          -  Either sex;&#xD;
&#xD;
          -  The participant /parents or guardian of the participant properly informed about the&#xD;
             study and having signed the informed consent form (ICF);&#xD;
&#xD;
          -  Participant/Parents' or guardian's availability for the entire period of the study and&#xD;
             reachability by study staff for post-vaccination follow-up&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Exclusion Criteria for Inoculation of the First Dose:&#xD;
&#xD;
        Whether the participant should be enrolled should be judged according to the following&#xD;
        criteria. The participant cannot participate in the study if any of the following&#xD;
        circumstances exists:&#xD;
&#xD;
          1. Previous history of hand, foot and mouth disease;&#xD;
&#xD;
          2. Allergy history to vaccine or components of the vaccine, previous history of asthma,&#xD;
             serious adverse effects of the vaccine such as urticaria, dyspnea, angioneurotic edema&#xD;
             or stomachache, etc;&#xD;
&#xD;
          3. Congenital malformation or developmental disorder, genetic defect, serious&#xD;
             malnutrition, etc;&#xD;
&#xD;
          4. Autoimmune disease or immunodeficiency or immunosuppression;&#xD;
&#xD;
          5. Severe neurological disorders (epilepsy, convulsion or tic) or family history of&#xD;
             mental disease;&#xD;
&#xD;
          6. History of thyroidectomy, or asplenia or functional asplenia;&#xD;
&#xD;
          7. Severely malnourished children&#xD;
&#xD;
          8. Abnormal coagulation functions (such as coagulation factor deficiency, blood&#xD;
             coagulation disease and blood platelet disorders) or obvious bruise or blood&#xD;
             coagulation disorders diagnosed by the doctors;&#xD;
&#xD;
          9. Received immunosuppressant therapy, cytotoxic drug therapy and inhaled corticosteroid&#xD;
             therapy (excluding the corticosteroid aerosol therapy for allergic rhinitis and&#xD;
             surface corticosteroid therapy for acute non-complicated dermatitis) in the past 6&#xD;
             months;&#xD;
&#xD;
         10. Received blood products within 3 months before receiving the investigational vaccine;&#xD;
&#xD;
         11. Received other study drugs or vaccines within 30 days before receiving the&#xD;
             investigational vaccine;&#xD;
&#xD;
         12. Received live attenuated vaccines within 14 days before receiving the investigational&#xD;
             vaccine;&#xD;
&#xD;
         13. Received subunit or inactivated vaccines within 7 days before receiving the&#xD;
             investigational vaccine;&#xD;
&#xD;
         14. Various acute diseases or acute exacerbation of chronic diseases within 7 days;&#xD;
&#xD;
         15. Fever before vaccine inoculation, axillary temperature &gt;37.5°C;&#xD;
&#xD;
         16. Any other factors which are unsuitable for participation in the clinical trial as&#xD;
             judged by the investigator.&#xD;
&#xD;
        Exclusion Criteria for Inoculation of the Second Dose of Vaccine:&#xD;
&#xD;
          1. Any serious adverse event related to the inoculation of the investigational product;&#xD;
&#xD;
          2. Hypersensitivity after vaccine inoculation (including urticaria/rash appeared within&#xD;
             30 minutes after inoculation);&#xD;
&#xD;
          3. Any confirmed or suspected autoimmune disease or immunodeficiency disease, including&#xD;
             human immunodeficiency virus (HIV) infection;&#xD;
&#xD;
          4. If acute or newly onset chronic disease occurs during vaccine inoculation;&#xD;
&#xD;
          5. The investigator judged that other significant reactions occur (including serious&#xD;
             pain, serious swelling, serious activity limitation, continuous hyperthermia, serious&#xD;
             headache or other systemic or local reactions);&#xD;
&#xD;
          6. The patient develops acute disease when vaccine is inoculated (acute diseases means&#xD;
             the moderate or severe disease with or without fever);&#xD;
&#xD;
          7. Axillary temperature &gt;37.5°C when vaccine is inoculated;&#xD;
&#xD;
          8. The patient has received subunit inactivated vaccine within 7 days or live attenuated&#xD;
             vaccines within 14 days.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Months</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Wasif Ali Khan, MBBS, MHS</last_name>
    <role>Principal Investigator</role>
    <affiliation>International Centre for Diarrhoeal Disease Research, Bangladesh</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Icddr,B</name>
      <address>
        <city>Dhaka</city>
        <zip>1000</zip>
        <country>Bangladesh</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Bangladesh</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>June 25, 2020</study_first_submitted>
  <study_first_submitted_qc>July 7, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 13, 2020</study_first_posted>
  <last_update_submitted>February 1, 2021</last_update_submitted>
  <last_update_submitted_qc>February 1, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 2, 2021</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>Hand, Foot and Mouth Disease</mesh_term>
    <mesh_term>Foot-and-Mouth Disease</mesh_term>
    <mesh_term>Mouth Diseases</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/NCT04467541
org study id: PR-19055
nct id: NCT04467541
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
1. Burden: Hand-foot-and-mouth disease (HFMD) characterized by skin rash in extremities,
           mouth ulcer and fever among <5 years children.Primarily caused by Enterovirus-
           predominantly human Enterovirus (EV) 71 and Coxsackie virus (CoxA). Several large
           epidemics have been reported worldwide.Large Asia-Pacific epidemic-in China in 2008,
           approximately 490,000 infections and 126 deaths of children. EV71 contributes severe and
           fatal cases e.g. encephalitis.A recent outbreak of HFMD in Bhubaneswar, Odisha in India
           indicates there is a chance of HFMD outbreaks in Bangladesh. However there is not much
           report of HFMD from Bangladesh.

        2. Knowledge gap: EV71 is most commonly transmitted via close person-to-person contact.
           Since there is no known effective treatment for HFMD and as the causative virus is
           highly contagious, hand washing is the best defense for prevention. However,
           asymptomatic or mild nature of the infection leads to ineffectiveness of public health
           interventions like hand washing. Thus the symptomatic management remains the mainstay of
           treatment strategy for HFMD as of now. EV71 vaccine, an inactivated vaccine, developed
           by Sinovac Biotech Ltd has shown satisfactory safety and effectiveness through Phase III
           trials conducted in various regions of mainland China, This new vaccine has the
           potential to significantly reduce suffering and death from EV71 disease in China.
           However, it is not assessed on Bangladeshi child.

        3. Relevance: Due to the absence of effective public health strategy and proper treatment,
           the development of an effective vaccine may be the best way to control EV71 infection.
General objective:

        1. To evaluate the safety of EV71 vaccine in adults and in children age 6-71 months

        2. To evaluate the immunogenicity of the vaccine in children by assessing the
           neutralization antibody levels before immunization; then 7, 15, 30 days after the first
           inoculation; and also 7, 15, 30 days after the second inoculation.

        3. To assess the incidence rate of adverse reactions/events

      Specific objective: To find out:

        1. Seroconversion rate of neutralization antibody on the day 30 after the whole-range
           immunization (i.e. after 2nd dose of vaccination);

        2. Positive rate and Geometric Mean Titer of neutralization antibody on the day 30 after
           the whole-range immunization;

        3. Seroconversion rate, positive rate and Geometric Mean Titer of serum neutralization
           antibody on the day 7, day 15, day 30 after the first inoculation;

        4. Seroconversion rate,positive rate and Geometric Mean Titer of serum neutralization
           antibody on the day 7, day 15 after the second inoculation;

        5. The incidence rate of adverse reactions & serious adverse events during the observation
           period of safety;

        6. The incidence rate of adverse reactions 0-30 days after each inoculation of vaccine;

        7. The incidence rate of adverse events 0-7 days after each inoculation of vaccine;
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Neutralizing Antibody responses for evaluation of enterovirus 71( EV71) vaccines
time frame: before immunization, 7, 15, 30 days after the first inoculation, 7, 15, 30 days after the second inoculation
description: Testing the neutralization antibody levels before immunization, 7, 15, 30 days after Ist inoculation, 7, 15, 30 days after the 2nd inoculation, calculate the positive seroconversion rate, the positive rate and geometric mean titre of neutralization antibody.
Vaccine recipients will have greater increase in neutralization antibody titers (NT) after the first dose, without a further increase in NT after the second dose. The seroconversion rate will be increased after Ist & second inoculation
Detection Method of the Anti-EV71 Neutralizing Antibody
Sample collection and processing
Serum will be examined to determine the potency of the neutralizing antibody
Treatment of the serum to be examined
Dilution of the serum to be examined and virus used for neutralization:
Serum and virus neutralizing and virus culture
Observation of the cytopathic change and judgment results
measure: Safety Outcome
time frame: After Ist vacctination (0 day) & 30 days after 2nd vaccination
description: Solicited AE's (Local) e.g. Tenderness, Indurations, Redness, swelling Rash (Injection site), Pruritus with Grading & Solicited AE's (Systemic) e.g. Allergic Reaction, Fatigue, Asthenia, Dysphoria, Loss of Appetite Nausea, Vomiting, Diarrhea Fever (Axillary Temp)with Grading will be assessed.
If any solicited or unsolicited AE's following vaccination in this study and will record adverse events at home in diary card.
arm group label: Inactivated enterovirus type 71 vaccine
arm group type: Experimental
description: Inactivated enterovirus type 71 vaccine safety in healthy adults followed by safety and immunogenicity administered in two consecutive doses, one-month apart among children aged 6 to 71 months
intervention type: Biological
intervention name: Inactivated Enterovirus Type 71 (EV71) Vaccine (Vero Cell)
description: Inactivated Enterovirus Type 71 (EV71) Vaccine safety in healthy adults followed by safety and immunogenicity administered in two consecutive doses, one-month apart among children aged 6 to 71 months
arm group label: Inactivated enterovirus type 71 vaccine
other name: Inlive
criteria: 
gender: All
minimum age: 6 Months
maximum age: 45 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Wasif Ali Khan, MBBS, MHS
role: Principal Investigator
affiliation: International Centre for Diarrhoeal Disease Research, Bangladesh
facility: 
country: Bangladesh
responsible party type: Sponsor
mesh term: Hand, Foot and Mouth Disease
mesh term: Foot-and-Mouth Disease
mesh term: Mouth Diseases