Prevention Of Respiratory Tract Infection And Covid-19 Through BCG Vaccination In Vulnerable Older Adults (BCG-PRIME)
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|ClinicalTrials.gov Identifier: NCT04537663|
Recruitment Status : Completed
First Posted : September 3, 2020
Last Update Posted : September 23, 2022
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|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||6112 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Masking Description:||Placebo consists of intradermal injection of sterile 0.9% NaCl.|
|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|
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.
Intradermal injection of sterile 0.9% NaCl.
- 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).
- 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.
- Cumulative incidence of asymptomatic, mild/moderate, and severe (requiring hospitalization) SARS-CoV-2 infection. [ Time Frame: 180 days ]
- 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.
- An acute respiratory tract infection [ Time Frame: 180 days ]Meeting the definition stated in the primary outcome. Irrespective of requiring an intervention.
- Medically attended acute respiratory tract infection [ Time Frame: 180 days ]Meeting the definition stated in the primary outcome including the requirement of an intervention.
- Acute respiratory tract infection related hospital admission [ Time Frame: 180 days ]Meeting the definition stated in the primary outcome including the need of hospitalization.
- Pneumonia diagnosed by a GP or medical specialist [ Time Frame: 180 days ]
- 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)
- Serious adverse events and adverse events. [ Time Frame: 180 days ]
- Major cardiovascular events [ Time Frame: 180 days ]
- All cause 6-month mortality [ Time Frame: 180 days ]
- History of falls [ Time Frame: 180 days ]
- 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
- 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)
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 ClinicalTrials.gov identifier (NCT number): NCT04537663
|Principal Investigator:||Marc Bonten, MD, PhD.||UMC Utrecht|
|Study Chair:||Mihai Netea, MD, PhD||Radboud University Medical Center|