<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/NCT03296423</url>
  </required_header>
  <id_info>
    <org_study_id>ACTIVATE</org_study_id>
    <nct_id>NCT03296423</nct_id>
  </id_info>
  <brief_title>Bacillus Calmette-guérin Vaccination to Prevent Infections of the Elderly</brief_title>
  <acronym>ACTIVATE</acronym>
  <official_title>A Randomized Clinical Trial for Enhanced Trained Immune Responses Through Bacillus Calmette-guérin Vaccination to Prevent Infections of the Elderly</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hellenic Institute for the Study of Sepsis</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Radboud University Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Hellenic Institute for the Study of Sepsis</source>
  <oversight_info>
    <has_dmc>No</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>
      One small recent trial in elderly volunteers showed that BCG vaccination can protect against&#xD;
      infectious complications, while several studies have demonstrated an increased capacity of&#xD;
      innate immune responses to react against pathogens. This process, also called trained&#xD;
      immunity, generates the hypothesis that BCG vaccination can prevent or delay new infections&#xD;
      in the elderly patients and is studied in the ACTIVATE trial&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In an era of antimicrobial resistance, where the already existing antimicrobials are not&#xD;
      sufficient, the development of new strategies for the prevention and treatment of infections&#xD;
      is of great interest. This approach becomes more and more mandatory in our current era of the&#xD;
      financial crisis where bacterial infections by multidrug-resistant emerge and impose heavily&#xD;
      on the financial burden of the disease. These infections occur more frequently among elderly&#xD;
      patients leading to prolonged hospitalization where unfavorable outcome is not infrequent1.&#xD;
      Vaccination is the traditional approach of infection prevention. A classic example focusing&#xD;
      on the need to prevent morbid re-infection is vaccination with pneumococcal vaccine the&#xD;
      incidence of pneumococcal pneumonia and bacteremia is enormously increasing among the&#xD;
      elderly2. The principle of vaccination is to develop memory B-lymphocytes so that early and&#xD;
      adequate antibody titers are produced upon re-exposure to the same antigen. This is called&#xD;
      the memory function of the adaptive immune system.&#xD;
&#xD;
      Well before adaptive immunity develops proper recognition of a bacterial pathogen is done&#xD;
      through binding of well-preserved structures known as pathogen-associated molecular patterns&#xD;
      (PAMPs) on pattern-recognition receptors (PRRs) of the innate immune system and mainly of&#xD;
      blood monocytes and tissue macrophages. Through a series of experiments in cell systems and&#xD;
      animals, it was found that exposure of macrophages to small amounts of PAMPs like the&#xD;
      β-glucan of Candida albicans and constituents of Mycobacterium tuberculosis may prevent death&#xD;
      upon re-exposure to lethal bacterial challenges like C.albicans and Staphylococcus aureus3-6.&#xD;
      Initial exposure to small amounts of PAMPs leads to epigenetic changes that induce the&#xD;
      capacity of macrophages and monocytes to produce high amounts of pro-inflammatory cytokines&#xD;
      like tumour necrosis factor-alpha (TNFα) and interferon-gamma (IFNγ) that clear efficiently&#xD;
      the pathogen3. This enhancement of the immune cells reaction after appropriate priming to&#xD;
      stimuli totally different from the initial ones is called trained immunity and it could be a&#xD;
      potential pathway of preventing serious infections without having severe adverse effects.&#xD;
&#xD;
      The concept has also been tested in healthy volunteers that were vaccinated with placebo or&#xD;
      BCG (Baccillus Calmette Guérin) vaccine. These volunteers were injected 14 days latter a&#xD;
      tri-valent influenza A vaccine. Volunteers previous vaccinated by BCG developed significantly&#xD;
      greater titers against hemagglutinin A of the influenza A virus whereas their circulating&#xD;
      monocytes were more potent for the production of IFNγ7. Finally, a small study has recently&#xD;
      reported that BCG vaccination of the elderly may protect against infections8, but larger&#xD;
      studies are necessary to confirm these findings. This generates hopes that vaccination by BCG&#xD;
      may increase immune resistance and/or tolerance of elderly patients upon exposure to&#xD;
      bacterial infections.&#xD;
&#xD;
      This generates hopes that vaccination by BCG may increase immune tolerance of elderly&#xD;
      patients upon exposure to bacterial diseases.&#xD;
&#xD;
      The aim of the study is to demonstrate in a double-blind, placebo-controlled approach if&#xD;
      vaccination of elderly patients with BCG vaccine may modulate their disease susceptibility&#xD;
      for bacterial diseases. This will be validated using both clinical and immunological&#xD;
      criteria.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 21, 2017</start_date>
  <completion_date type="Actual">November 30, 2020</completion_date>
  <primary_completion_date type="Actual">August 31, 2020</primary_completion_date>
  <phase>Phase 4</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>
    <intervention_model_description>Patients vaccinated with placebo or BCG</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Time to first infection</measure>
    <time_frame>12 months</time_frame>
    <description>The time interval to the first infection post hospital discharge between the two groups of treatment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Hospitalization</measure>
    <time_frame>Month 12</time_frame>
    <description>The rate of hospitalizations will be compared between the two groups of treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to first infection or sepsis episode</measure>
    <time_frame>Month 12</time_frame>
    <description>The time to first infection or sepsis episode will be compared between the two groups of treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total number of infections</measure>
    <time_frame>Month 12</time_frame>
    <description>The total number of infections will be compared between the two groups of treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to first hospitalization</measure>
    <time_frame>Month 12</time_frame>
    <description>The time to first hospitalization will be compared between the two groups of treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of antibiotic administrations</measure>
    <time_frame>Month 12</time_frame>
    <description>The number of antibiotic administrations will be compared between the two groups of treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>Month 12</time_frame>
    <description>Mortality will be compared between the two groups of treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cytokine stimulation</measure>
    <time_frame>Month 3</time_frame>
    <description>Cytokine stimulation from peripheral blood monuclear cells will be compared between the two groups of treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Epigenetic changes</measure>
    <time_frame>Month 3</time_frame>
    <description>Epigenetic changes of circulating monocytes will be compared between the two groups of treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cost of treatment</measure>
    <time_frame>Month 12</time_frame>
    <description>The effect of BCG vaccination on cost of treatment for infections will be compared between the two groups of treatment</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">200</enrollment>
  <condition>Infection</condition>
  <condition>Hospitalization</condition>
  <condition>Mortality</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>One intradermal injection of 0.1ml of sodium chloride 0.9%</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Vaccination</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>One intradermal injection of 0.1ml of BCG (BCG vaccine Bulgaria strain 1331; Intervax)</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Vaccination</intervention_name>
    <description>Patients discharged from hospital will be vaccinated with one intradermal injection of 0.1ml of BCG vaccine</description>
    <arm_group_label>Vaccination</arm_group_label>
    <other_name>BCG</other_name>
    <other_name>Intervax</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Patients discharged from hospital will be vaccinated with one intradermal injection of 0.1ml of sodium chloride 0.9%</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Saline</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female&#xD;
&#xD;
          -  Age more than or equal to 65 years based on the precise date of birth&#xD;
&#xD;
          -  Discharge from hospital after hospitalization for a medical cause. All medical causes&#xD;
             make patients eligible for enrolment with the only exception of medical causes&#xD;
             mentioned in the exclusion criteria&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Failure to obtain written informed consent&#xD;
&#xD;
          -  Solid organ malignancy or lymphoma diagnosed the last five years&#xD;
&#xD;
          -  Treatment with oral or intravenous steroids defined as daily doses of 10mg prednisone&#xD;
             or equivalent for longer than 3 months&#xD;
&#xD;
          -  Severely immunocompromised patients. This exclusion category comprises: a) patients&#xD;
             with known infection by the human immunodeficiency virus (HIV-1); b) neutropenic&#xD;
             patients with less than 500 neutrophils/mm3; c) patients with solid organ&#xD;
             transplantation; d) patients with bone marrow transplantation; e) patients under&#xD;
             chemotherapy; f) patients with primary immunodeficiency; g) severe lymphopenia with&#xD;
             less than 400 lymphocytes/mm3; h) treatment with any anti-cytokine therapies&#xD;
&#xD;
          -  Positive Interferon-gamma Release Assay (IGRA)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>65 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Antonios Papadopoulos, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>National and Kapodistrian University of Athens</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>4th Department of Internal Medicine, ATTIKON University Hospital</name>
      <address>
        <city>Athens</city>
        <state>Attiki</state>
        <zip>12462</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Greece</country>
  </location_countries>
  <reference>
    <citation>Leentjens J, Kox M, Stokman R, Gerretsen J, Diavatopoulos DA, van Crevel R, Rimmelzwaan GF, Pickkers P, Netea MG. BCG Vaccination Enhances the Immunogenicity of Subsequent Influenza Vaccination in Healthy Volunteers: A Randomized, Placebo-Controlled Pilot Study. J Infect Dis. 2015 Dec 15;212(12):1930-8. doi: 10.1093/infdis/jiv332. Epub 2015 Jun 12.</citation>
    <PMID>26071565</PMID>
  </reference>
  <reference>
    <citation>Blok BA, Arts RJ, van Crevel R, Benn CS, Netea MG. Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines. J Leukoc Biol. 2015 Sep;98(3):347-56. doi: 10.1189/jlb.5RI0315-096R. Epub 2015 Jul 6.</citation>
    <PMID>26150551</PMID>
  </reference>
  <verification_date>January 2021</verification_date>
  <study_first_submitted>September 20, 2017</study_first_submitted>
  <study_first_submitted_qc>September 23, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 28, 2017</study_first_posted>
  <last_update_submitted>January 8, 2021</last_update_submitted>
  <last_update_submitted_qc>January 8, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">January 11, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>BCG vaccination</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
    <mesh_term>Communicable Diseases</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/NCT03296423
org study id: ACTIVATE
nct id: NCT03296423
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
One small recent trial in elderly volunteers showed that BCG vaccination can protect against
      infectious complications, while several studies have demonstrated an increased capacity of
      innate immune responses to react against pathogens. This process, also called trained
      immunity, generates the hypothesis that BCG vaccination can prevent or delay new infections
      in the elderly patients and is studied in the ACTIVATE trial
In an era of antimicrobial resistance, where the already existing antimicrobials are not
      sufficient, the development of new strategies for the prevention and treatment of infections
      is of great interest. This approach becomes more and more mandatory in our current era of the
      financial crisis where bacterial infections by multidrug-resistant emerge and impose heavily
      on the financial burden of the disease. These infections occur more frequently among elderly
      patients leading to prolonged hospitalization where unfavorable outcome is not infrequent1.
      Vaccination is the traditional approach of infection prevention. A classic example focusing
      on the need to prevent morbid re-infection is vaccination with pneumococcal vaccine the
      incidence of pneumococcal pneumonia and bacteremia is enormously increasing among the
      elderly2. The principle of vaccination is to develop memory B-lymphocytes so that early and
      adequate antibody titers are produced upon re-exposure to the same antigen. This is called
      the memory function of the adaptive immune system.

      Well before adaptive immunity develops proper recognition of a bacterial pathogen is done
      through binding of well-preserved structures known as pathogen-associated molecular patterns
      (PAMPs) on pattern-recognition receptors (PRRs) of the innate immune system and mainly of
      blood monocytes and tissue macrophages. Through a series of experiments in cell systems and
      animals, it was found that exposure of macrophages to small amounts of PAMPs like the
      β-glucan of Candida albicans and constituents of Mycobacterium tuberculosis may prevent death
      upon re-exposure to lethal bacterial challenges like C.albicans and Staphylococcus aureus3-6.
      Initial exposure to small amounts of PAMPs leads to epigenetic changes that induce the
      capacity of macrophages and monocytes to produce high amounts of pro-inflammatory cytokines
      like tumour necrosis factor-alpha (TNFα) and interferon-gamma (IFNγ) that clear efficiently
      the pathogen3. This enhancement of the immune cells reaction after appropriate priming to
      stimuli totally different from the initial ones is called trained immunity and it could be a
      potential pathway of preventing serious infections without having severe adverse effects.

      The concept has also been tested in healthy volunteers that were vaccinated with placebo or
      BCG (Baccillus Calmette Guérin) vaccine. These volunteers were injected 14 days latter a
      tri-valent influenza A vaccine. Volunteers previous vaccinated by BCG developed significantly
      greater titers against hemagglutinin A of the influenza A virus whereas their circulating
      monocytes were more potent for the production of IFNγ7. Finally, a small study has recently
      reported that BCG vaccination of the elderly may protect against infections8, but larger
      studies are necessary to confirm these findings. This generates hopes that vaccination by BCG
      may increase immune resistance and/or tolerance of elderly patients upon exposure to
      bacterial infections.

      This generates hopes that vaccination by BCG may increase immune tolerance of elderly
      patients upon exposure to bacterial diseases.

      The aim of the study is to demonstrate in a double-blind, placebo-controlled approach if
      vaccination of elderly patients with BCG vaccine may modulate their disease susceptibility
      for bacterial diseases. This will be validated using both clinical and immunological
      criteria.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Patients vaccinated with placebo or BCG
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Time to first infection
time frame: 12 months
description: The time interval to the first infection post hospital discharge between the two groups of treatment.
measure: Hospitalization
time frame: Month 12
description: The rate of hospitalizations will be compared between the two groups of treatment
measure: Time to first infection or sepsis episode
time frame: Month 12
description: The time to first infection or sepsis episode will be compared between the two groups of treatment
measure: Total number of infections
time frame: Month 12
description: The total number of infections will be compared between the two groups of treatment
measure: Time to first hospitalization
time frame: Month 12
description: The time to first hospitalization will be compared between the two groups of treatment
measure: Number of antibiotic administrations
time frame: Month 12
description: The number of antibiotic administrations will be compared between the two groups of treatment
measure: Mortality
time frame: Month 12
description: Mortality will be compared between the two groups of treatment
measure: Cytokine stimulation
time frame: Month 3
description: Cytokine stimulation from peripheral blood monuclear cells will be compared between the two groups of treatment
measure: Epigenetic changes
time frame: Month 3
description: Epigenetic changes of circulating monocytes will be compared between the two groups of treatment
measure: Cost of treatment
time frame: Month 12
description: The effect of BCG vaccination on cost of treatment for infections will be compared between the two groups of treatment
arm group label: Placebo
arm group type: Placebo Comparator
description: One intradermal injection of 0.1ml of sodium chloride 0.9%
arm group label: Vaccination
arm group type: Active Comparator
description: One intradermal injection of 0.1ml of BCG (BCG vaccine Bulgaria strain 1331; Intervax)
intervention type: Biological
intervention name: Vaccination
description: Patients discharged from hospital will be vaccinated with one intradermal injection of 0.1ml of BCG vaccine
arm group label: Vaccination
other name: BCG
other name: Intervax
intervention type: Biological
intervention name: Placebo
description: Patients discharged from hospital will be vaccinated with one intradermal injection of 0.1ml of sodium chloride 0.9%
arm group label: Placebo
other name: Saline
criteria: 
gender: All
minimum age: 65 Years
maximum age: N/A
healthy volunteers: No
last name: Antonios Papadopoulos, MD, PhD
role: Principal Investigator
affiliation: National and Kapodistrian University of Athens
facility: 
country: Greece
citation: Leentjens J, Kox M, Stokman R, Gerretsen J, Diavatopoulos DA, van Crevel R, Rimmelzwaan GF, Pickkers P, Netea MG. BCG Vaccination Enhances the Immunogenicity of Subsequent Influenza Vaccination in Healthy Volunteers: A Randomized, Placebo-Controlled Pilot Study. J Infect Dis. 2015 Dec 15;212(12):1930-8. doi: 10.1093/infdis/jiv332. Epub 2015 Jun 12.
PMID: 26071565
citation: Blok BA, Arts RJ, van Crevel R, Benn CS, Netea MG. Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines. J Leukoc Biol. 2015 Sep;98(3):347-56. doi: 10.1189/jlb.5RI0315-096R. Epub 2015 Jul 6.
PMID: 26150551
responsible party type: Sponsor
mesh term: Infections
mesh term: Communicable Diseases
sharing ipd: No