<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/NCT04475302</url>
  </required_header>
  <id_info>
    <org_study_id>2020010</org_study_id>
    <nct_id>NCT04475302</nct_id>
  </id_info>
  <brief_title>BCG Vaccine in Reducing Morbidity and Mortality in Elderly Individuals in COVID-19 Hotspots</brief_title>
  <official_title>Study to Evaluate the Effectiveness of BCG Vaccine in Reducing Morbidity and Mortality in Elderly Individuals in COVID-19 Hotspots in India</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Tuberculosis Research Centre, India</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>ICMR-National Institute for Research in Tuberculosis, Chennai, Tamil Nadu</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>All India Institute of Medical Sciences, New Delhi</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute for Research in Environmental Health, Bhopal, Madhya Pradesh</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute of Occupational Health, Ahmedabad, Gujarat</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>King Edward Memorial Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute for Implementation Research on Non-Communicable Disease</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Tuberculosis Research Centre, India</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>
      Rationale: SARS-CoV2 viral infection is spreading rapidly throughout the world and in India&#xD;
      the epidemic poses a major threat to the public health system. Elderly individuals,&#xD;
      especially those with diabetes, hypertension, other chronic diseases are at high risk of&#xD;
      mortality. Strategies to protect these individuals are desperately needed to safeguard&#xD;
      continuous patient care. Bacille Calmette-Guérin (BCG) is a vaccine against tuberculosis,&#xD;
      with protective non-specific effects against other respiratory tract infections in in-vitro&#xD;
      and in-vivo studies, and reported significant reductions in morbidity and mortality. Based on&#xD;
      the capacity of BCG to reduce the incidence of respiratory tract infections in children and&#xD;
      adults, to exert antiviral effects in experimental models; and to reduce viremia in an&#xD;
      experimental human model of viral infection, the hypothesis is that BCG vaccination will&#xD;
      partially protect against mortality in high-risk, elderly individuals.&#xD;
&#xD;
      Primary Objective: To evaluate the effectiveness of BCG vaccination in preventing morbidity&#xD;
      and mortality due to COVID-19 in elderly individuals aged between 60 to 80 years living in&#xD;
      COVID-19 hotspots in India.&#xD;
&#xD;
      Secondary objectives:&#xD;
&#xD;
        1. To evaluate the effectiveness of BCG vaccination in terms of&#xD;
&#xD;
             1. reducing the cumulative incidence of hospital admission and Intensive Care&#xD;
                admission&#xD;
&#xD;
             2. reducing the incidence of other respiratory febrile illness&#xD;
&#xD;
        2. To determine the innate and adaptive immune responses, IgM, IgG and IgA antibody titers&#xD;
           generated by BCG vaccination (both total and SARS-Cov2 specific) in a subset of&#xD;
           individuals.&#xD;
&#xD;
        3. To measure biomarkers induced by BCG vaccination as correlates of risk/protection&#xD;
           against SARS-Cov2 in a subset of individuals&#xD;
&#xD;
      Method and Analysis:&#xD;
&#xD;
      Study design: Intervention study Study population: Elderly 60 - 80 years of age residing in&#xD;
      designated hotspots for SARS-Cov2 infection Study Intervention: One dose of 0.1ml BCG&#xD;
      vaccine, given intradermally. Elderly individuals not vaccinated from the same hotspot area&#xD;
      or from neighbouring hotspot wards areas will be considered as the controls. Study sites:&#xD;
      Chennai, Mumbai, Ahmedabad, Bhopal, Jodhpur and New Delhi. Study Sample size: 1450&#xD;
      individuals between 60-80 years of age will receive BCG vaccination while 725 individuals&#xD;
      will be controls without vaccination Study duration: 6 months/participant. Enrolment at each&#xD;
      site will be over: 4 months. Each participant will be followed for 6 months post vaccination.&#xD;
      Primary Outcome Measures: During the study period (6-months), Proportion of individuals&#xD;
      receiving the BCG vaccination who are asymptomatic but become PCR-positive or seroconvert&#xD;
      during the 6-month of study period. Proportion of patients with development of COVID-19&#xD;
      disease (either PCR-positive or seroconvert with symptoms) during the study period.&#xD;
      Proportion of patients with Severe COVID-19 disease and death due to Covid-19 disease&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Recruitment area: Under the Lockdown 2.0, the country has been classified into three key&#xD;
      zones-Red, Orange and Green (26). These zones will support the cluster containment plan&#xD;
      announced by the government, while opening up the rest of the places.&#xD;
&#xD;
      Green Zone: Places which have so far not reported even a single COVID-19 positive case will&#xD;
      be declared as Green Zone under Government's new plan. This means nearly 400+ districts of&#xD;
      India might qualify to be tagged as Green Zone.&#xD;
&#xD;
      Orange Zone: Orange zone may see opening of limited public transport and also allow&#xD;
      exemptions for essential services personnel and farming and harvest activity for the ongoing&#xD;
      season. Orange zone will have less than 15 cases of COVID-19.&#xD;
&#xD;
      Red Zone: A district or cluster declared as a red zone, will see severe restrictions with&#xD;
      zero or no activity allowed. Typical understanding is that any place with more than 15&#xD;
      COVID-19 positive cases can be declared as a red zone. Investigators will include the Red &amp;&#xD;
      Orange zones of Delhi, Madhya Pradesh, Maharashtra, Gujarat, Tamilnadu, Rajasthan and other&#xD;
      interested states for this study.&#xD;
&#xD;
      Recruitment methods: Participants would be recruited through (i) information presented in&#xD;
      community organizations, hospitals, colleges and other institutions to the general public.&#xD;
      (ii) From a line list prepared of adults above the age of 60 years from Census data for the&#xD;
      hotspot areas. (iii) Participants will also be recruited by use of an advertisement +/-&#xD;
      registration form formally approved by the ethics committee(s) and distributed or posted in&#xD;
      the&#xD;
&#xD;
        1. newspapers or other literature for circulation.&#xD;
&#xD;
        2. Via presentations (e.g. presentations at lectures or invited seminars). (iv) Community&#xD;
           Advisory Board will be created for this study and help of the members of this board will&#xD;
           be taken for recruitment to the study Interested individuals will be provided detailed&#xD;
           information about the study and the requirements for participation will be provided.&#xD;
           Participants will be given brochure about the study and patient information sheet. They&#xD;
           will have the opportunity to ask any questions they might have and to talk to a study&#xD;
           team member. If they are still interested and willing to participate, they will be&#xD;
           invited to participate in screening evaluation procedure.&#xD;
&#xD;
      Study Procedures: Participants meeting inclusion criteria will be recruited in a&#xD;
      nonrandomized manner after obtaining their consent to participate to the study. An&#xD;
      information document that clearly indicates the risks and the benefits associated with the&#xD;
      participation to the study will be given to each patient before signing consent. Regarding&#xD;
      participant identification, a study number will be assigned sequentially to included&#xD;
      participants, according to the range of patient numbers allocated to each study center.&#xD;
&#xD;
      Participants will be seen at baseline for enrolment, initial data collection (a detailed&#xD;
      medical history including h/o previous BCG vaccination and evidence of BCG vaccination scar&#xD;
      to be noted), Chest x-ray PA view to rule out PTB, blood sampling for antibody testing (2 ml)&#xD;
      and PCR (nasopharyngeal swab).&#xD;
&#xD;
      Eligible participants will be administered BCG at day 0. Participants will be followed up&#xD;
      weekly by phone for first 2 months and asked to complete a standardized questionnaire. Month&#xD;
      1, 3 &amp; 6 will be visit in person while Month 2 &amp; 5 will be completed over phone. Participants&#xD;
      would be tested for COVID antibodies at month 3 and month 6. If positive, nasal/throat swab&#xD;
      would be collected for PCR testing for confirmation. Participants will also be asked to call&#xD;
      the study staff in the event of any adverse reactions or illness. Participants will&#xD;
      thereafter be followed up monthly for six months.&#xD;
&#xD;
      Participants will be given a diary card (paper), with instructions to fill in case of adverse&#xD;
      events, along with the emergency 24 hour telephone number to contact the on-call study&#xD;
      physician if needed. They will be instructed on how to self-assess the severity of these AEs.&#xD;
      There will also be space on the diary card to self-document unsolicited AEs, and whether&#xD;
      medication was taken to relieve the symptoms.&#xD;
&#xD;
      In addition to blood, nasopharyngeal swabs will be collected from all participants.&#xD;
&#xD;
      qRT- PCR test will be considered to reconfirm the qRT-PCR positive / negative status at&#xD;
      enrolment. In a subset of this cohort (15% of the sample), consenting for immunological&#xD;
      substudy, 20 ml of blood will be collected at baseline for immunological and biomarker&#xD;
      analysis. They will also provide additional blood samples (20 ml) at 1, 3 and 6 months post&#xD;
      vaccination for immunological and biomarker studies.&#xD;
&#xD;
      Blood collection: Investigators will collect 2 ml of venous blood after obtaining consent&#xD;
      from participants. Investigators will collect the specimen using a syringe following all the&#xD;
      safety precautions and transfer the specimen to serum separator tubes. After completion of&#xD;
      sample collection from all eligible participants, the specimen will be transported to the&#xD;
      nearest District Public Health Laboratory (DPHL)/Virus Research and Diagnostic Laboratory&#xD;
      Network (VRDLN) laboratory in cold chain. In the laboratory, serum will be separated and used&#xD;
      for rapid antibody testing. Detection of SARS-CoV 2 specific antibodies will be performed&#xD;
      using a ICMR validated SARS-CoV-2 Antibody Test. The Lateral Flow-based&#xD;
      immune-chromatographic test detects SARS-CoV 2 specific antibodies (IgG/IgM) with a&#xD;
      turnaround time of 15-20 mins. Presence of coloured bands at Test and Control lines will&#xD;
      indicate the presence of SARS-CoV-2 antibodies (positive result) in the specimen. Absence of&#xD;
      coloured band in Test line will indicate the absence of SARS-CoV-2 antibodies (negative&#xD;
      result).&#xD;
&#xD;
      Immunology analysis: The primary variables of interest of immune response to vaccines will be&#xD;
      the percentage of CD4+ and CD8+ T cells that express IFN-γ, TNF, IL-2, IL-17, IL-22, CD107a,&#xD;
      Perforin, Granzyme B and Granulysin alone or in combination in response to stimulation with&#xD;
      SARS-Cov-2 and BCG antigens. Secondary variables of interest would be the response of trained&#xD;
      monocytes and other innate immune cells including NK cells, NKT cells, gd T cells and MAIT&#xD;
      cells. Response will be measured by flow cytometry in the intracellular cytokine staining&#xD;
      (ICS) assay. Blood collected for immunological studies will be utilized as follows: PBMC&#xD;
      isolation and storage for immunology studies described above; Whole blood in Lithium Heparin&#xD;
      microtainer for absolute blood cell counting by flow cytometry (deconvolution for&#xD;
      transcriptomics) and for Interferon Gamma Release Assays; plasma and serum for soluble immune&#xD;
      mediators by ELISA and for total and SARS-Cov2 specific IgG, IgM and IgA ELISA.&#xD;
&#xD;
      Diagnostic tests:&#xD;
&#xD;
      PCR: Molecular diagnosis of SARS-Cov2 will be done by using RT-PCR kits according the ICMR&#xD;
      guidelines. Serology: Antibody IgG/IgM Covid-19 rapid test kit will be used. Chest x-ray&#xD;
      along with symptom screening: To rule out tuberculosis&#xD;
&#xD;
      Subgroup Analysis&#xD;
&#xD;
        1. The primary analysis will be performed using the whole cohort&#xD;
&#xD;
        2. A stratified analysis will be undertaken for various age groups and by risk groups based&#xD;
           on co-morbidity. This will allow vaccine effectiveness to be assess in more homogeneous&#xD;
           subgroups and to check for effect of modification across strata&#xD;
&#xD;
        3. Stratified analysis will also be done for various geographic distribution and occupation&#xD;
&#xD;
        4. Immunological analysis will be carried out in a subset of individuals (n=200)&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 1, 2020</start_date>
  <completion_date type="Actual">September 20, 2021</completion_date>
  <primary_completion_date type="Actual">September 20, 2021</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>In this study, as we are employing a control group that is not vaccinated against the disease to be prevented, but some clinical data are available to support the likely efficacy of the candidate vaccine, we will use unbalanced randomization and enrol participants to control group in the ratio of 2:1, so that majority of the study participant will receive the vaccine</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Mortality due to COVID-19 disease</measure>
    <time_frame>6 months from study start date</time_frame>
    <description>Number of deaths due to COVID-19 disease</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Hospital admission and ICU admission due to Covid-19, Severity of Covid-19 (mild, moderate or severe), Hospital admission due to other respiratory febrile illness, immunological outcomes in the sub study</measure>
    <time_frame>10 months from study start date</time_frame>
    <description>Number of hospital admissions and ICU admissions due to Covid-19 and other respiratory disease, Number of COVID-19 cases reported based on severity level (mild, moderate or severe) and immunological outcomes in the sub study (baseline and at 1, 3 and 6 months post vaccination).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">2175</enrollment>
  <condition>COVID</condition>
  <arm_group>
    <arm_group_label>Intervention arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>In the identified hotspots, BCG vaccine will be offered to all the elderly between 60 - 80 years of age. Those who get vaccinated will be followed for a period of 6-months.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control arm</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>in the hotspots, those who do not agree for vaccination, will be considered as controls. They will have an entry and exit interview at baseline and end of study period&#xD;
in situations where we are unable to enrol the required number of controls from the vaccination hotspot zones, then hotspots in the neighbouring area / wards where BCG is not offered will be taken as control sites. Elderly between 60-80 years in those areas would be considered as control sites for the study. The elderly participants will be approached for an entry and exit interview, if they agree. If they do not agree for an exit interview at the end of 6-months, then the status of those in the control group would be collected either from the corporation records / other medical database.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>BCG vaccine (Freeze-dried)</intervention_name>
    <description>single dose of BCG vaccine (Freeze-dried) manufactured by Serum Institute of India, Pune. The composition of BCG vaccine is Live, attenuated BCG (Bacillus Calmette-Guerin Strain). (Each 1 ml contains between 2 x 106 and 8 x 106 Colony Forming Units (C.F.U.) with Diluent: Sodium Chloride Injection I.P.)</description>
    <arm_group_label>Intervention arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adults 60 years of age or older (&lt;100 years) with general good health, as confirmed by&#xD;
             history and physical examination.&#xD;
&#xD;
          -  No known history of HIV or on immunosuppressive drugs for malignancy or transplant&#xD;
&#xD;
          -  Provide a signed and dated informed consent form&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Positive for SARS-Cov2 infection&#xD;
&#xD;
          -  Known HIV or other immune-suppressive treatments for malignancy or transplant&#xD;
&#xD;
          -  Recently diagnosed as TB or currently on anti-TB treatment or anti-psychiatric&#xD;
             medications&#xD;
&#xD;
          -  Has any BCG vaccine contraindication&#xD;
&#xD;
          -  H/o of previous administration of experimental MTB vaccines within the past 6 months.&#xD;
&#xD;
          -  Sick and moribund individuals with Karnofsky score &lt;50&#xD;
&#xD;
               -  Elderly individuals with or without co-morbid conditions like Diabetes mellitus,&#xD;
                  or Hypertension or Hyperlipidemia will be considered for this study, if they are&#xD;
                  on regular treatment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>60 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Padmapriyadarsini Chandrasekaran, MBBS,DNB,MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Institute for Research in Tuberculosis</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Anant Mohan</last_name>
    <role>Principal Investigator</role>
    <affiliation>All India Institute of Medical Sciences, New Delhi</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Randeep Guleria</last_name>
    <role>Principal Investigator</role>
    <affiliation>All India Institute of Medical Sciences, New Delhi</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Tiwari R R.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Institute for Research in Environmental Health</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Yogesh Sabde</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Institute for Research in Environmental Health</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Kamalesh Sarkar</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Institute of Occupational Health</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Asha Keetharam</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Institute of Occupational Health</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Hemant Deshmukh</last_name>
    <role>Principal Investigator</role>
    <affiliation>KEM Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Rujuta Hadaye</last_name>
    <role>Principal Investigator</role>
    <affiliation>GSMC and KEM Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Toteja G.S.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Institute for Implementation Research on Non-Communicable Disease</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Subash Babu, MBBS, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>NIH-International Center for Excellence in Research</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Tuberculosis Research Centre</name>
      <address>
        <city>Chennai</city>
        <state>Tamilnadu</state>
        <zip>600031</zip>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>India</country>
  </location_countries>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>July 16, 2020</study_first_submitted>
  <study_first_submitted_qc>July 16, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 17, 2020</study_first_posted>
  <last_update_submitted>July 7, 2022</last_update_submitted>
  <last_update_submitted_qc>July 7, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">July 8, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>BCG Vaccine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT04475302
org study id: 2020010
nct id: NCT04475302
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Rationale: SARS-CoV2 viral infection is spreading rapidly throughout the world and in India
      the epidemic poses a major threat to the public health system. Elderly individuals,
      especially those with diabetes, hypertension, other chronic diseases are at high risk of
      mortality. Strategies to protect these individuals are desperately needed to safeguard
      continuous patient care. Bacille Calmette-Guérin (BCG) is a vaccine against tuberculosis,
      with protective non-specific effects against other respiratory tract infections in in-vitro
      and in-vivo studies, and reported significant reductions in morbidity and mortality. Based on
      the capacity of BCG to reduce the incidence of respiratory tract infections in children and
      adults, to exert antiviral effects in experimental models; and to reduce viremia in an
      experimental human model of viral infection, the hypothesis is that BCG vaccination will
      partially protect against mortality in high-risk, elderly individuals.

      Primary Objective: To evaluate the effectiveness of BCG vaccination in preventing morbidity
      and mortality due to COVID-19 in elderly individuals aged between 60 to 80 years living in
      COVID-19 hotspots in India.

      Secondary objectives:

        1. To evaluate the effectiveness of BCG vaccination in terms of

             1. reducing the cumulative incidence of hospital admission and Intensive Care
                admission

             2. reducing the incidence of other respiratory febrile illness

        2. To determine the innate and adaptive immune responses, IgM, IgG and IgA antibody titers
           generated by BCG vaccination (both total and SARS-Cov2 specific) in a subset of
           individuals.

        3. To measure biomarkers induced by BCG vaccination as correlates of risk/protection
           against SARS-Cov2 in a subset of individuals

      Method and Analysis:

      Study design: Intervention study Study population: Elderly 60 - 80 years of age residing in
      designated hotspots for SARS-Cov2 infection Study Intervention: One dose of 0.1ml BCG
      vaccine, given intradermally. Elderly individuals not vaccinated from the same hotspot area
      or from neighbouring hotspot wards areas will be considered as the controls. Study sites:
      Chennai, Mumbai, Ahmedabad, Bhopal, Jodhpur and New Delhi. Study Sample size: 1450
      individuals between 60-80 years of age will receive BCG vaccination while 725 individuals
      will be controls without vaccination Study duration: 6 months/participant. Enrolment at each
      site will be over: 4 months. Each participant will be followed for 6 months post vaccination.
      Primary Outcome Measures: During the study period (6-months), Proportion of individuals
      receiving the BCG vaccination who are asymptomatic but become PCR-positive or seroconvert
      during the 6-month of study period. Proportion of patients with development of COVID-19
      disease (either PCR-positive or seroconvert with symptoms) during the study period.
      Proportion of patients with Severe COVID-19 disease and death due to Covid-19 disease
Recruitment area: Under the Lockdown 2.0, the country has been classified into three key
      zones-Red, Orange and Green (26). These zones will support the cluster containment plan
      announced by the government, while opening up the rest of the places.

      Green Zone: Places which have so far not reported even a single COVID-19 positive case will
      be declared as Green Zone under Government's new plan. This means nearly 400+ districts of
      India might qualify to be tagged as Green Zone.

      Orange Zone: Orange zone may see opening of limited public transport and also allow
      exemptions for essential services personnel and farming and harvest activity for the ongoing
      season. Orange zone will have less than 15 cases of COVID-19.

      Red Zone: A district or cluster declared as a red zone, will see severe restrictions with
      zero or no activity allowed. Typical understanding is that any place with more than 15
      COVID-19 positive cases can be declared as a red zone. Investigators will include the Red &
      Orange zones of Delhi, Madhya Pradesh, Maharashtra, Gujarat, Tamilnadu, Rajasthan and other
      interested states for this study.

      Recruitment methods: Participants would be recruited through (i) information presented in
      community organizations, hospitals, colleges and other institutions to the general public.
      (ii) From a line list prepared of adults above the age of 60 years from Census data for the
      hotspot areas. (iii) Participants will also be recruited by use of an advertisement +/-
      registration form formally approved by the ethics committee(s) and distributed or posted in
      the

        1. newspapers or other literature for circulation.

        2. Via presentations (e.g. presentations at lectures or invited seminars). (iv) Community
           Advisory Board will be created for this study and help of the members of this board will
           be taken for recruitment to the study Interested individuals will be provided detailed
           information about the study and the requirements for participation will be provided.
           Participants will be given brochure about the study and patient information sheet. They
           will have the opportunity to ask any questions they might have and to talk to a study
           team member. If they are still interested and willing to participate, they will be
           invited to participate in screening evaluation procedure.

      Study Procedures: Participants meeting inclusion criteria will be recruited in a
      nonrandomized manner after obtaining their consent to participate to the study. An
      information document that clearly indicates the risks and the benefits associated with the
      participation to the study will be given to each patient before signing consent. Regarding
      participant identification, a study number will be assigned sequentially to included
      participants, according to the range of patient numbers allocated to each study center.

      Participants will be seen at baseline for enrolment, initial data collection (a detailed
      medical history including h/o previous BCG vaccination and evidence of BCG vaccination scar
      to be noted), Chest x-ray PA view to rule out PTB, blood sampling for antibody testing (2 ml)
      and PCR (nasopharyngeal swab).

      Eligible participants will be administered BCG at day 0. Participants will be followed up
      weekly by phone for first 2 months and asked to complete a standardized questionnaire. Month
      1, 3 & 6 will be visit in person while Month 2 & 5 will be completed over phone. Participants
      would be tested for COVID antibodies at month 3 and month 6. If positive, nasal/throat swab
      would be collected for PCR testing for confirmation. Participants will also be asked to call
      the study staff in the event of any adverse reactions or illness. Participants will
      thereafter be followed up monthly for six months.

      Participants will be given a diary card (paper), with instructions to fill in case of adverse
      events, along with the emergency 24 hour telephone number to contact the on-call study
      physician if needed. They will be instructed on how to self-assess the severity of these AEs.
      There will also be space on the diary card to self-document unsolicited AEs, and whether
      medication was taken to relieve the symptoms.

      In addition to blood, nasopharyngeal swabs will be collected from all participants.

      qRT- PCR test will be considered to reconfirm the qRT-PCR positive / negative status at
      enrolment. In a subset of this cohort (15% of the sample), consenting for immunological
      substudy, 20 ml of blood will be collected at baseline for immunological and biomarker
      analysis. They will also provide additional blood samples (20 ml) at 1, 3 and 6 months post
      vaccination for immunological and biomarker studies.

      Blood collection: Investigators will collect 2 ml of venous blood after obtaining consent
      from participants. Investigators will collect the specimen using a syringe following all the
      safety precautions and transfer the specimen to serum separator tubes. After completion of
      sample collection from all eligible participants, the specimen will be transported to the
      nearest District Public Health Laboratory (DPHL)/Virus Research and Diagnostic Laboratory
      Network (VRDLN) laboratory in cold chain. In the laboratory, serum will be separated and used
      for rapid antibody testing. Detection of SARS-CoV 2 specific antibodies will be performed
      using a ICMR validated SARS-CoV-2 Antibody Test. The Lateral Flow-based
      immune-chromatographic test detects SARS-CoV 2 specific antibodies (IgG/IgM) with a
      turnaround time of 15-20 mins. Presence of coloured bands at Test and Control lines will
      indicate the presence of SARS-CoV-2 antibodies (positive result) in the specimen. Absence of
      coloured band in Test line will indicate the absence of SARS-CoV-2 antibodies (negative
      result).

      Immunology analysis: The primary variables of interest of immune response to vaccines will be
      the percentage of CD4+ and CD8+ T cells that express IFN-γ, TNF, IL-2, IL-17, IL-22, CD107a,
      Perforin, Granzyme B and Granulysin alone or in combination in response to stimulation with
      SARS-Cov-2 and BCG antigens. Secondary variables of interest would be the response of trained
      monocytes and other innate immune cells including NK cells, NKT cells, gd T cells and MAIT
      cells. Response will be measured by flow cytometry in the intracellular cytokine staining
      (ICS) assay. Blood collected for immunological studies will be utilized as follows: PBMC
      isolation and storage for immunology studies described above; Whole blood in Lithium Heparin
      microtainer for absolute blood cell counting by flow cytometry (deconvolution for
      transcriptomics) and for Interferon Gamma Release Assays; plasma and serum for soluble immune
      mediators by ELISA and for total and SARS-Cov2 specific IgG, IgM and IgA ELISA.

      Diagnostic tests:

      PCR: Molecular diagnosis of SARS-Cov2 will be done by using RT-PCR kits according the ICMR
      guidelines. Serology: Antibody IgG/IgM Covid-19 rapid test kit will be used. Chest x-ray
      along with symptom screening: To rule out tuberculosis

      Subgroup Analysis

        1. The primary analysis will be performed using the whole cohort

        2. A stratified analysis will be undertaken for various age groups and by risk groups based
           on co-morbidity. This will allow vaccine effectiveness to be assess in more homogeneous
           subgroups and to check for effect of modification across strata

        3. Stratified analysis will also be done for various geographic distribution and occupation

        4. Immunological analysis will be carried out in a subset of individuals (n=200)
allocation: Non-Randomized
intervention model: Single Group Assignment
intervention model description: In this study, as we are employing a control group that is not vaccinated against the disease to be prevented, but some clinical data are available to support the likely efficacy of the candidate vaccine, we will use unbalanced randomization and enrol participants to control group in the ratio of 2:1, so that majority of the study participant will receive the vaccine
primary purpose: Prevention
masking: None (Open Label)
measure: Mortality due to COVID-19 disease
time frame: 6 months from study start date
description: Number of deaths due to COVID-19 disease
measure: Hospital admission and ICU admission due to Covid-19, Severity of Covid-19 (mild, moderate or severe), Hospital admission due to other respiratory febrile illness, immunological outcomes in the sub study
time frame: 10 months from study start date
description: Number of hospital admissions and ICU admissions due to Covid-19 and other respiratory disease, Number of COVID-19 cases reported based on severity level (mild, moderate or severe) and immunological outcomes in the sub study (baseline and at 1, 3 and 6 months post vaccination).
arm group label: Intervention arm
arm group type: Experimental
description: In the identified hotspots, BCG vaccine will be offered to all the elderly between 60 - 80 years of age. Those who get vaccinated will be followed for a period of 6-months.
arm group label: Control arm
arm group type: No Intervention
description: in the hotspots, those who do not agree for vaccination, will be considered as controls. They will have an entry and exit interview at baseline and end of study period
in situations where we are unable to enrol the required number of controls from the vaccination hotspot zones, then hotspots in the neighbouring area / wards where BCG is not offered will be taken as control sites. Elderly between 60-80 years in those areas would be considered as control sites for the study. The elderly participants will be approached for an entry and exit interview, if they agree. If they do not agree for an exit interview at the end of 6-months, then the status of those in the control group would be collected either from the corporation records / other medical database.
intervention type: Biological
intervention name: BCG vaccine (Freeze-dried)
description: single dose of BCG vaccine (Freeze-dried) manufactured by Serum Institute of India, Pune. The composition of BCG vaccine is Live, attenuated BCG (Bacillus Calmette-Guerin Strain). (Each 1 ml contains between 2 x 106 and 8 x 106 Colony Forming Units (C.F.U.) with Diluent: Sodium Chloride Injection I.P.)
arm group label: Intervention arm
criteria: 
gender: All
minimum age: 60 Years
maximum age: 80 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Padmapriyadarsini Chandrasekaran, MBBS,DNB,MS
role: Principal Investigator
affiliation: National Institute for Research in Tuberculosis
last name: Anant Mohan
role: Principal Investigator
affiliation: All India Institute of Medical Sciences, New Delhi
last name: Randeep Guleria
role: Principal Investigator
affiliation: All India Institute of Medical Sciences, New Delhi
last name: Tiwari R R.
role: Principal Investigator
affiliation: National Institute for Research in Environmental Health
last name: Yogesh Sabde
role: Principal Investigator
affiliation: National Institute for Research in Environmental Health
last name: Kamalesh Sarkar
role: Principal Investigator
affiliation: National Institute of Occupational Health
last name: Asha Keetharam
role: Principal Investigator
affiliation: National Institute of Occupational Health
last name: Hemant Deshmukh
role: Principal Investigator
affiliation: KEM Hospital
last name: Rujuta Hadaye
role: Principal Investigator
affiliation: GSMC and KEM Hospital
last name: Toteja G.S.
role: Principal Investigator
affiliation: National Institute for Implementation Research on Non-Communicable Disease
last name: Subash Babu, MBBS, PhD
role: Principal Investigator
affiliation: NIH-International Center for Excellence in Research
facility: 
country: India
responsible party type: Sponsor
mesh term: BCG Vaccine
sharing ipd: No