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Prevention Of Respiratory Tract Infection And Covid-19 Through BCG Vaccination In Vulnerable Older Adults (BCG-PRIME)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT04537663
Recruitment Status : Completed
First Posted : September 3, 2020
Last Update Posted : September 23, 2022
Information provided by (Responsible Party):
MJM Bonten, UMC Utrecht

Brief Summary:

On March 11 2020 the World Health Organization (WHO) declared the coronavirus (SARS-CoV-2) outbreak a pandemic. Worldwide, the number of confirmed cases continues to rise, leading to significant morbidity and mortality. In the Netherlands, although the incidence is currently low due to social distancing measures, recurrence of infections is expected once measures are going to be lifted. Although individuals of any age can acquire SARS-CoV-2, adults of middle and older age are at highest risk for developing severe COVID-19 disease. Moreover, recent reports demonstrate that mortality rates rise significantly among patients 60 years and older. Therefore, strategies to prevent SARS-CoV-2 infection or to reduce its clinical consequences in vulnerable populations are urgently needed. Bacille Calmette-Guérin (BCG) vaccine not only protects against tuberculosis, but also induces protection against various respiratory infections, including those with a viral etiology. We hypothesize that BCG vaccination reduces clinically relevant respiratory tract infections requiring medical intervention, including COVID-19, in vulnerable elderly.

The objective of this trial is to determine the impact of BCG vaccination on the incidence of clinically relevant respiratory infections or COVID-19 in vulnerable elderly.

The trial is designed as an adaptive multi-center double-blind randomized placebo-controlled trial. The attempt is to include 5,200 to 7,000 vulnerable elderly, defined as ≥60 years of age being discharged from hospital in the last 6 weeks, or visiting a medical outpatient clinic, thrombosis care services, or chronic renal replacement departments. Patients with contraindications to BCG vaccination as stipulated in the Summary of Product Characteristics (SPC) and patients with a history of COVID-19 will be excluded. Participants will be randomized between intracutaneous administration of BCG vaccine (Danish strain 1331) or placebo (0.1ml 0.9% NaCl) in a 1:1 ratio.The trial has an adaptive primary endpoint. Based on accrual of the two endpoints, the primary endpoint will be either (a) COVID-19 or (b) clinically relevant respiratory tract infection requiring medical intervention, potentially including COVID-19 episodes. The other will be declared secondary endpoint. Other secondary endpoints include: all SARS-CoV-2 infections (including asymptomatic infections), influenza infection, acute respiratory infection (ARI; all infections regardless of medical intervention), ARI-related hospital admission, COVID-19 related hospital admission, pneumonia, mental, physical and social functioning, serious adverse events and adverse events, and death.

Condition or disease Intervention/treatment Phase
Respiratory Tract Infections Covid19 Drug: Bacille Calmette-Guérin (BCG) Drug: Placebo Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6112 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Placebo consists of intradermal injection of sterile 0.9% NaCl.
Primary Purpose: Prevention
Official Title: Bacillus Calmette-Guérin Vaccination to Prevent Serious Respiratory Tract Infection and Covid-19 in Vulnerable Elderly - an Adaptive randoMized controllEd Trial
Actual Study Start Date : September 7, 2020
Actual Primary Completion Date : July 8, 2021
Actual Study Completion Date : July 8, 2021

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Bacille Calmette-Guérin (BCG)
Intradermal injection of BCG-Vaccine SSI [Statens Serum Institut]) - Danish strain 1331.
Drug: Bacille Calmette-Guérin (BCG)
Participants in the intervention group will be vaccinated with the licensed BCG vaccine (Danish strain 1331, SSI, Denmark) using the standard vaccination technique for this vaccine (intradermal injection in the left upper arm).

Placebo Comparator: Placebo
Intradermal injection of sterile 0.9% NaCl.
Drug: Placebo
Intradermal injection of sterile 0.9% NaCl.

Primary Outcome Measures :
  1. The trial has an adaptive primary endpoint. Based on predefined objective and quantitative criteria the primary endpoint will be either a clinically relevant respiratory tract infection, or COVID-19. [ Time Frame: 180 days ]

    Clinically relevant relevant respiratory tract infection is composed of clinical symptoms in combination with the need for medical intervention. Exact criteria for clinically relevant respiratory tract infection and COVID-19 are described in the protocol.

    A blinded adjudication committee will determine the status of the primary endpoints of all participants with a potential primary endpoint, based on information provided in a standardized narrative using data reported by the participant and from GP and hospital medical records when relevant. For detection of ARI, symptoms are checked on a weekly (from week 1-4) or bi-weekly basis (from week 4 onward).

Secondary Outcome Measures :
  1. Cumulative incidence of SARS-CoV-2 infection (irrespective the presence of symptoms) [ Time Frame: 180 days ]
    Cumulative incidence of SARS-CoV-2 infection regardless of symptomatology defined as having had COVID-19 as described under primary endpoints above and/or SARS-CoV-2 positive test in real time as part of the test-and-trace program of the Dutch government and/of documented SARS-CoV-2 seroconversion at 6 months. Seroconversion will be defined as antibody-positive at 6 months but negative at baseline.

  2. Cumulative incidence of asymptomatic, mild/moderate, and severe (requiring hospitalization) SARS-CoV-2 infection. [ Time Frame: 180 days ]
  3. Influenza infection [ Time Frame: 180 days ]
    Defined as either of 1) ARI + microbiological evidence of influenza infection, 2) seroconversion of influenza between enrolment and month 6.

  4. An acute respiratory tract infection [ Time Frame: 180 days ]
    Meeting the definition stated in the primary outcome. Irrespective of requiring an intervention.

  5. Medically attended acute respiratory tract infection [ Time Frame: 180 days ]
    Meeting the definition stated in the primary outcome including the requirement of an intervention.

  6. Acute respiratory tract infection related hospital admission [ Time Frame: 180 days ]
    Meeting the definition stated in the primary outcome including the need of hospitalization.

  7. Pneumonia diagnosed by a GP or medical specialist [ Time Frame: 180 days ]
  8. Functioning in daily activities [ Time Frame: 180 days ]
    Using the Katz Activities of Daily Living (ADL) scale, from A (fully independent) to G (dependent in feeding, continence, transferring, going to toilet, dressing, and bathing)

  9. Serious adverse events and adverse events. [ Time Frame: 180 days ]
  10. Major cardiovascular events [ Time Frame: 180 days ]
  11. All cause 6-month mortality [ Time Frame: 180 days ]
  12. History of falls [ Time Frame: 180 days ]
  13. Quality of life using the EQ5D quality of life instrument [ Time Frame: 180 days ]
    Using the EQ5D quality of life instrument, with questions on 4 domains (mobility, self-care, usual activities, pain discomfort) and the percepted health of the participant with 100 meaning the best health you can imagine, and 0 meaning the worst health you can imagine

  14. Activities in daily living [ Time Frame: 180 days ]
    Using the 6-item Lawton Activities of Daily Living questionnaire, with scores ranging from 0 (low function, dependent) to 8 (high function, independent) for women (0 through 5 for men)

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   60 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Age ≥60 years
  • Having a chronic disease or having undergone major surgery
  • Meeting at least one of the following criteria:

    1. Planned to be discharged from the hospital or discharged from the hospital less than 6 weeks ago; a hospital admission is defined as an overnight stay. Departments of interest are those that in the opinion of the principle investigator admit mostly vulnerable elderly and include but are not limited to: cardiology, pulmonology, internal medicine, neurology.
    2. Visiting a medical outpatient clinic
    3. Attending the thrombosis care service

Exclusion Criteria:

  • Fever (>38 ºC) within the past 24 hours
  • Suspicion of current active viral or bacterial infection; the requirement to finish an antibiotic course upon discharge is not an exclusion criterion when the infection is controlled in the opinion of the attending physician
  • Vaccination with live vaccine in the past four weeks or planned vaccination with live vaccine during the next four weeks
  • Severely immunocompromised participants. This exclusion category comprises:

    1. known infection by the human immunodeficiency virus (HIV-1);
    2. neutropenic with less than 500 neutrophils/mm3;
    3. solid organ transplantation;
    4. bone marrow transplantation;
    5. hematological malignancy;
    6. chemo-, radio- or immunotherapy for solid organ malignancy in the past 6 months;
    7. primary immunodeficiency;
    8. severe lymphopenia with less than 400 lymphocytes/mm3;
    9. treatment with any immunosuppressant drugs such as anti-cytokine therapies, and treatment with oral or intravenous steroids defined as daily doses of >10 mg/day or a cumulative dose of >700 mg prednisone or equivalent for other corticosteroids, or probable use of oral or intravenous steroids in the following four weeks
  • Known history of a positive Mantoux or active TB; prior BCG vaccination is NOT an exclusion criterion.
  • Born in a country with high incidence of TB; a list of non-eligible countries will be created by the trial steering committee prior to the first enrolment.
  • Active participation in another research study that involves BCG administration
  • History of documented COVID-19 (self-reported by the participant: either confirmed by a microbiological test or with clinical diagnosis during hospitalization)
  • Not able to perform the study procedures as judged by the attending physician
  • Legally incapacitated or unwilling to provide informed consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04537663

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Sponsors and Collaborators
UMC Utrecht
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Principal Investigator: Marc Bonten, MD, PhD. UMC Utrecht
Study Chair: Mihai Netea, MD, PhD Radboud University Medical Center
  Study Documents (Full-Text)

Documents provided by MJM Bonten, UMC Utrecht:
Statistical Analysis Plan  [PDF] January 13, 2021

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Responsible Party: MJM Bonten, Prof. dr., UMC Utrecht Identifier: NCT04537663    
Other Study ID Numbers: BCG-PRIME
First Posted: September 3, 2020    Key Record Dates
Last Update Posted: September 23, 2022
Last Verified: September 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by MJM Bonten, UMC Utrecht:
Bacillus Calmette-Guerin
Additional relevant MeSH terms:
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Communicable Diseases
Respiratory Tract Infections
Disease Attributes
Pathologic Processes
Pneumonia, Viral
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases