<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/NCT04439045</url>
  </required_header>
  <id_info>
    <org_study_id>20-5413</org_study_id>
    <nct_id>NCT04439045</nct_id>
  </id_info>
  <brief_title>Efficacy and Safety of VPM1002 in Reducing SARS-CoV-2 (COVID-19) Infection Rate and Severity</brief_title>
  <acronym>COBRA</acronym>
  <official_title>A Randomized, Double-blind, Placebo-controlled Phase 3 Study: Efficacy and Safety of VPM1002 in Reducing SARS-CoV-2 Infection Rate and COVID-19 Severity</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Health Network, Toronto</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Serum Institute of India Pvt. Ltd.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Max Planck Institute for Infection Biology</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Verity Pharmaceuticals Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University Health Network, Toronto</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>
      Bacille Calmette-Guerin (BCG) is a live attenuated vaccine administered for prevention of&#xD;
      tuberculosis. Recently, several groups have hypothesized that BCG may &quot;train&quot; the immune&#xD;
      system to respond to a variety of unrelated infections, including viruses and in particular&#xD;
      the coronavirus responsible for COVID-19. Trials are currently being conducted in Australia,&#xD;
      Netherlands, Germany and the United Kingdom to evaluate its effectiveness.&#xD;
&#xD;
      Front line workers includes members of municipal and provincial police services, emergency&#xD;
      medical personnel, firefighters, public transport employees, health service workers and food&#xD;
      manufacturing employees. They are at high risk of infection from COVID-19, with potentially&#xD;
      high infection rate. The investigators propose an interventional trial to evaluate the&#xD;
      effectiveness of BCG vaccination to prevent COVID-19 infection and reduce its severity in&#xD;
      front-line employees in Ontario.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 24, 2020</start_date>
  <completion_date type="Actual">September 9, 2021</completion_date>
  <primary_completion_date type="Actual">September 9, 2021</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>Double (Participant, Care Provider)</masking>
    <masking_description>The clinical trial is designed as a double-blind (observer blind) study. Observer-blind means that during the course of trial, the companions/parents/guardians of the subjects and the study personnel responsible for the evaluation of any study endpoint will be unaware which vaccine was administered.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>COVID-19 infection</measure>
    <time_frame>7 months</time_frame>
    <description>To compare the self-reported incidence of SARS-CoV-2 infection (confirmed by positive test) following vaccination with either VPM1002 or placebo.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of hospitalization for COVID-19</measure>
    <time_frame>7 months</time_frame>
    <description>To compare the incidence of hospitalization in participants with positive COVID-19 test treated with either VPM1002 or placebo</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of ICU admission for COVID-19</measure>
    <time_frame>7 months</time_frame>
    <description>To compare the incidence of hospitalization requiring intensive care (ICU admission) in participants with positive COVID-19 test treated with either VPM1002 or placebo</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of ARDS</measure>
    <time_frame>7 months</time_frame>
    <description>To compare the incidence of acute respiratory distress syndrome (ARDS) in participants with positive COVID-19 test treated with either VPM1002 or placebo.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mechanical ventilation for COVID-19</measure>
    <time_frame>7 months</time_frame>
    <description>To compare the incidence of the need for mechanical ventilation in participants with positive COVID-19 test treated with either VPM1002 or placebo.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Secondary infection in COVID-19</measure>
    <time_frame>7 months</time_frame>
    <description>To compare the incidence of secondary infection in participants with positive COVID-19 test treated with either VPM1002 or placebo.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>COVID-19-related Mortality</measure>
    <time_frame>7 months</time_frame>
    <description>To compare the mortality in participants with positive COVID-19 test treated with either VPM1002 or placebo.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of DVT</measure>
    <time_frame>7 months</time_frame>
    <description>To compare the incidence of deep vein thrombosis, pulmonary embolism, or stroke in participants with positive COVID-19 test treated with either VPM1002 or placebo.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Incidence of COVID-19 in Participants with Past BCG Vaccination</measure>
    <time_frame>7 months</time_frame>
    <description>To compare the incidence of COVID-19 in participants who have received BCG vaccination previously vs those not previously vaccinated</description>
  </other_outcome>
  <other_outcome>
    <measure>Measure cardiac troponin, B-type natriuretic peptide, N-terminal pro b-type natriuretic peptide, C reactive protein, serum amyloid A, and procalcitonin as biomarkers of COVID-19</measure>
    <time_frame>7 months</time_frame>
    <description>To measure cardiac troponin, B-type natriuretic peptide, N-terminal pro b-type natriuretic peptide, C reactive protein, serum amyloid A, and procalcitonin identified as potential biomarkers of COVID-19 infection using blood samples collected prior to the vaccination and at the end of the 7-month follow-up.</description>
  </other_outcome>
  <other_outcome>
    <measure>Adverse events following BCG vaccine</measure>
    <time_frame>7 months</time_frame>
    <description>To compare adverse event profile in participants following administration of VPM1002 or placebo when used for prevention of COVID-19.</description>
  </other_outcome>
  <other_outcome>
    <measure>Innate Trained Immunity</measure>
    <time_frame>7 months</time_frame>
    <description>Compare the priming of the innate trained immunity (i.e. induction of Th1 and Th17 responses to unrelated stimuli) in participants following administration of VPM1002 or placebo when used for prevention of COVID-19.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">122</enrollment>
  <condition>SARS-CoV-2 Infection</condition>
  <arm_group>
    <arm_group_label>VPM1002</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A single dose of 0.1 mL of the reconstituted vaccine containing VPM1002 (Mycobacterium bovis rBCGΔureC::hly, live 2-8 × 105 CFU), administered via intradermal injection.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>A single dose of 0.1 mL of the 0.9% sodium chloride injection, administered via intradermal injection.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>VPM1002</intervention_name>
    <description>VPM1002 is a recombinant BCG (rBCG)</description>
    <arm_group_label>VPM1002</arm_group_label>
    <other_name>Mycobacterium bovis rBCGΔureC::hly</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>0.9% sodium chloride</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>sodium chloride</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Eighteen years of age or older&#xD;
&#xD;
          -  Employee/member of: municipal or provincial police service, emergency medical&#xD;
             services, fire services, public transport service, health service, food manufacturing&#xD;
             facility&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior intravesical BCG or intradermal BCG, with the exception of tuberculosis&#xD;
             vaccination in childhood.&#xD;
&#xD;
          -  Previous known history of latent or active tuberculosis&#xD;
&#xD;
          -  Known kidney, liver or blood disorders which impairs organ and marrow function&#xD;
&#xD;
          -  Chronic administration of steroids (&gt;10 mg prednisone) at the time of randomization&#xD;
&#xD;
          -  Current or planned concomitant biologic therapy in the next 7 months.&#xD;
&#xD;
          -  Known hypersensitivity or allergy to components of VPM1002&#xD;
&#xD;
          -  Pregnant or planning to become pregnant in the future 7 months.&#xD;
&#xD;
          -  Breastfeeding.&#xD;
&#xD;
          -  Current suspected viral or bacterial infection.&#xD;
&#xD;
          -  Body temperature &gt; 38° C&#xD;
&#xD;
          -  Participation in another interventional study with potentially conflicting medication&#xD;
             within 30 days before screening.&#xD;
&#xD;
          -  The presence of an impaired immune response irrespective of whether this impairment is&#xD;
             congenital or caused by disease, drugs or other therapy (e.g., anti-TNF therapy,&#xD;
             methotrexate, azathioprine, antimalarials).&#xD;
&#xD;
          -  Active malignancy requiring treatment.&#xD;
&#xD;
          -  Known positive HIV serology.&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to BCG vaccine.&#xD;
&#xD;
          -  Previous positive COVID-19 confirmed infection.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness.&#xD;
&#xD;
          -  Psychiatric illness/social situations that would limit compliance with study&#xD;
             requirements.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Alexandre R Zlotta, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Health Network, Toronto</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Health Network</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 2M9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>June 3, 2020</study_first_submitted>
  <study_first_submitted_qc>June 18, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 19, 2020</study_first_posted>
  <last_update_submitted>April 13, 2022</last_update_submitted>
  <last_update_submitted_qc>April 13, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 15, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
    <mesh_term>Communicable Diseases</mesh_term>
    <mesh_term>COVID-19</mesh_term>
  </condition_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/NCT04439045
org study id: 20-5413
nct id: NCT04439045
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Bacille Calmette-Guerin (BCG) is a live attenuated vaccine administered for prevention of
      tuberculosis. Recently, several groups have hypothesized that BCG may "train" the immune
      system to respond to a variety of unrelated infections, including viruses and in particular
      the coronavirus responsible for COVID-19. Trials are currently being conducted in Australia,
      Netherlands, Germany and the United Kingdom to evaluate its effectiveness.

      Front line workers includes members of municipal and provincial police services, emergency
      medical personnel, firefighters, public transport employees, health service workers and food
      manufacturing employees. They are at high risk of infection from COVID-19, with potentially
      high infection rate. The investigators propose an interventional trial to evaluate the
      effectiveness of BCG vaccination to prevent COVID-19 infection and reduce its severity in
      front-line employees in Ontario.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Double (Participant, Care Provider)
masking description: The clinical trial is designed as a double-blind (observer blind) study. Observer-blind means that during the course of trial, the companions/parents/guardians of the subjects and the study personnel responsible for the evaluation of any study endpoint will be unaware which vaccine was administered.
measure: COVID-19 infection
time frame: 7 months
description: To compare the self-reported incidence of SARS-CoV-2 infection (confirmed by positive test) following vaccination with either VPM1002 or placebo.
measure: Incidence of hospitalization for COVID-19
time frame: 7 months
description: To compare the incidence of hospitalization in participants with positive COVID-19 test treated with either VPM1002 or placebo
measure: Incidence of ICU admission for COVID-19
time frame: 7 months
description: To compare the incidence of hospitalization requiring intensive care (ICU admission) in participants with positive COVID-19 test treated with either VPM1002 or placebo
measure: Incidence of ARDS
time frame: 7 months
description: To compare the incidence of acute respiratory distress syndrome (ARDS) in participants with positive COVID-19 test treated with either VPM1002 or placebo.
measure: Mechanical ventilation for COVID-19
time frame: 7 months
description: To compare the incidence of the need for mechanical ventilation in participants with positive COVID-19 test treated with either VPM1002 or placebo.
measure: Secondary infection in COVID-19
time frame: 7 months
description: To compare the incidence of secondary infection in participants with positive COVID-19 test treated with either VPM1002 or placebo.
measure: COVID-19-related Mortality
time frame: 7 months
description: To compare the mortality in participants with positive COVID-19 test treated with either VPM1002 or placebo.
measure: Incidence of DVT
time frame: 7 months
description: To compare the incidence of deep vein thrombosis, pulmonary embolism, or stroke in participants with positive COVID-19 test treated with either VPM1002 or placebo.
measure: Incidence of COVID-19 in Participants with Past BCG Vaccination
time frame: 7 months
description: To compare the incidence of COVID-19 in participants who have received BCG vaccination previously vs those not previously vaccinated
measure: Measure cardiac troponin, B-type natriuretic peptide, N-terminal pro b-type natriuretic peptide, C reactive protein, serum amyloid A, and procalcitonin as biomarkers of COVID-19
time frame: 7 months
description: To measure cardiac troponin, B-type natriuretic peptide, N-terminal pro b-type natriuretic peptide, C reactive protein, serum amyloid A, and procalcitonin identified as potential biomarkers of COVID-19 infection using blood samples collected prior to the vaccination and at the end of the 7-month follow-up.
measure: Adverse events following BCG vaccine
time frame: 7 months
description: To compare adverse event profile in participants following administration of VPM1002 or placebo when used for prevention of COVID-19.
measure: Innate Trained Immunity
time frame: 7 months
description: Compare the priming of the innate trained immunity (i.e. induction of Th1 and Th17 responses to unrelated stimuli) in participants following administration of VPM1002 or placebo when used for prevention of COVID-19.
arm group label: VPM1002
arm group type: Experimental
description: A single dose of 0.1 mL of the reconstituted vaccine containing VPM1002 (Mycobacterium bovis rBCGΔureC::hly, live 2-8 × 105 CFU), administered via intradermal injection.
arm group label: Placebo
arm group type: Placebo Comparator
description: A single dose of 0.1 mL of the 0.9% sodium chloride injection, administered via intradermal injection.
intervention type: Biological
intervention name: VPM1002
description: VPM1002 is a recombinant BCG (rBCG)
arm group label: VPM1002
other name: Mycobacterium bovis rBCGΔureC::hly
intervention type: Other
intervention name: Placebo
description: 0.9% sodium chloride
arm group label: Placebo
other name: sodium chloride
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Alexandre R Zlotta, MD PhD
role: Principal Investigator
affiliation: University Health Network, Toronto
facility: 
country: Canada
responsible party type: Sponsor
mesh term: Infections
mesh term: Communicable Diseases
mesh term: COVID-19
sharing ipd: No