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Bacillus Calmette-guérin Vaccination to Prevent Infections of the Elderly (ACTIVATE)

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ClinicalTrials.gov Identifier: NCT03296423
Recruitment Status : Completed
First Posted : September 28, 2017
Last Update Posted : January 11, 2021
Sponsor:
Collaborator:
Radboud University
Information provided by (Responsible Party):
Hellenic Institute for the Study of Sepsis

Tracking Information
First Submitted Date  ICMJE September 20, 2017
First Posted Date  ICMJE September 28, 2017
Last Update Posted Date January 11, 2021
Actual Study Start Date  ICMJE September 21, 2017
Actual Primary Completion Date August 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 23, 2017)
Time to first infection [ Time Frame: 12 months ]
The time interval to the first infection post hospital discharge between the two groups of treatment.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 23, 2017)
  • Hospitalization [ Time Frame: Month 12 ]
    The rate of hospitalizations will be compared between the two groups of treatment
  • Time to first infection or sepsis episode [ Time Frame: Month 12 ]
    The time to first infection or sepsis episode will be compared between the two groups of treatment
  • Total number of infections [ Time Frame: Month 12 ]
    The total number of infections will be compared between the two groups of treatment
  • Time to first hospitalization [ Time Frame: Month 12 ]
    The time to first hospitalization will be compared between the two groups of treatment
  • Number of antibiotic administrations [ Time Frame: Month 12 ]
    The number of antibiotic administrations will be compared between the two groups of treatment
  • Mortality [ Time Frame: Month 12 ]
    Mortality will be compared between the two groups of treatment
  • Cytokine stimulation [ Time Frame: Month 3 ]
    Cytokine stimulation from peripheral blood monuclear cells will be compared between the two groups of treatment
  • Epigenetic changes [ Time Frame: Month 3 ]
    Epigenetic changes of circulating monocytes will be compared between the two groups of treatment
  • Cost of treatment [ Time Frame: Month 12 ]
    The effect of BCG vaccination on cost of treatment for infections will be compared between the two groups of treatment
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Bacillus Calmette-guérin Vaccination to Prevent Infections of the Elderly
Official Title  ICMJE A Randomized Clinical Trial for Enhanced Trained Immune Responses Through Bacillus Calmette-guérin Vaccination to Prevent Infections of the Elderly
Brief Summary 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
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Patients vaccinated with placebo or BCG
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE
  • Infection
  • Hospitalization
  • Mortality
Intervention  ICMJE
  • Biological: Vaccination
    Patients discharged from hospital will be vaccinated with one intradermal injection of 0.1ml of BCG vaccine
    Other Names:
    • BCG
    • Intervax
  • Biological: Placebo
    Patients discharged from hospital will be vaccinated with one intradermal injection of 0.1ml of sodium chloride 0.9%
    Other Name: Saline
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    One intradermal injection of 0.1ml of sodium chloride 0.9%
    Intervention: Biological: Placebo
  • Active Comparator: Vaccination
    One intradermal injection of 0.1ml of BCG (BCG vaccine Bulgaria strain 1331; Intervax)
    Intervention: Biological: Vaccination
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 23, 2017)
200
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE November 30, 2020
Actual Primary Completion Date August 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male or female
  • Age more than or equal to 65 years based on the precise date of birth
  • Discharge from hospital after hospitalization for a medical cause. All medical causes make patients eligible for enrolment with the only exception of medical causes mentioned in the exclusion criteria

Exclusion Criteria:

  • Failure to obtain written informed consent
  • Solid organ malignancy or lymphoma diagnosed the last five years
  • Treatment with oral or intravenous steroids defined as daily doses of 10mg prednisone or equivalent for longer than 3 months
  • Severely immunocompromised patients. This exclusion category comprises: a) patients with known infection by the human immunodeficiency virus (HIV-1); b) neutropenic patients with less than 500 neutrophils/mm3; c) patients with solid organ transplantation; d) patients with bone marrow transplantation; e) patients under chemotherapy; f) patients with primary immunodeficiency; g) severe lymphopenia with less than 400 lymphocytes/mm3; h) treatment with any anti-cytokine therapies
  • Positive Interferon-gamma Release Assay (IGRA)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 65 Years and older   (Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Greece
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03296423
Other Study ID Numbers  ICMJE ACTIVATE
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Hellenic Institute for the Study of Sepsis
Study Sponsor  ICMJE Hellenic Institute for the Study of Sepsis
Collaborators  ICMJE Radboud University
Investigators  ICMJE
Principal Investigator: Antonios Papadopoulos, MD, PhD National and Kapodistrian University of Athens
PRS Account Hellenic Institute for the Study of Sepsis
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP