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Completed

NCT Number: NCT04537663

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

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.

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Key information

Conditions

Respiratory Tract Infections COVID-19 Coronaviridae Infections Coronavirus Infections Covid19 Infections Lung Diseases Nidovirales Infections Pneumonia Pneumonia, Viral RNA Virus Infections Respiratory Tract Diseases Virus Diseases

Age range

60 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Meander Medical Center, Amersfoort, Netherlands

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Age ≥60 years
  • Having a chronic disease or having undergone major surgery
  • Meeting at least one of the following criteria:
  • 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.
  • Visiting a medical outpatient clinic
  • 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:
  • known infection by the human immunodeficiency virus (HIV-1);
  • neutropenic with less than 500 neutrophils/mm3;
  • solid organ transplantation;
  • bone marrow transplantation;
  • hematological malignancy;
  • chemo-, radio- or immunotherapy for solid organ malignancy in the past 6 months;
  • primary immunodeficiency;
  • severe lymphopenia with less than 400 lymphocytes/mm3;
  • 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

Treatment and study plan

Bacille Calmette-Guérin (BCG)

Drug

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

Drug

Intradermal injection of sterile 0.9% NaCl.

Primary outcomes

  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 outcomes

  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)

Sponsors and collaborators

Lead sponsor

UMC Utrecht

Other

Registry information

Official study title

Bacillus Calmette-Guérin Vaccination to Prevent Serious Respiratory Tract Infection and Covid-19 in Vulnerable Elderly - an Adaptive randoMized controllEd Trial

Acronym: BCG-PRIME

Important dates

Study start
2020
Primary completion
2021
Study completion
2021
First posted
Sep 3, 2020
Registry last updated
Sep 23, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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