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

Covid19 Clinical Trial

— BCG-PRIME  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04537663
• Other study ID #: BCG-PRIME
• Status: Completed
• Phase: Phase 4
• Start date: September 7, 2020
• Est. completion date: July 8, 2021

Study information

• Verified date: September 2022
• Source: UMC Utrecht
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 6112
• Est. completion date: July 8, 2021
• Est. primary completion date: July 8, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Communicable Diseases
• COVID-19
• Covid19
• Infections
• Respiratory Tract Infections

Intervention

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
Intradermal injection of sterile 0.9% NaCl.

Locations

Country	Name	City	State
Netherlands	Meander Medical Center	Amersfoort
Netherlands	Amsterdam University Medical Center	Amsterdam
Netherlands	OLVG	Amsterdam
Netherlands	Rijnstate hospital	Arnhem
Netherlands	Amphia hospital	Breda
Netherlands	Hagahospital	Den Haag
Netherlands	Catharina hospital	Eindhoven
Netherlands	Zuyderland Hospital	Geleen
Netherlands	Martini hospital	Groningen
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Leiden University Medical Center	Leiden
Netherlands	Maastricht University Medical Center	Maastricht
Netherlands	St. Antonius hospital	Nieuwegein
Netherlands	Canisius-Wilhelmina Hospital	Nijmegen
Netherlands	Radboud University Medical Center	Nijmegen
Netherlands	Erasmus Medical Center	Rotterdam
Netherlands	Ikazia Hospital	Rotterdam
Netherlands	Maasstad Hospital	Rotterdam
Netherlands	Bernhoven hospital	Uden
Netherlands	University Medical Center Utrecht	Utrecht

Sponsors (1)

Lead Sponsor	Collaborator
UMC Utrecht

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	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).	180 days
Secondary	Cumulative incidence of SARS-CoV-2 infection (irrespective the presence of symptoms)	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.	180 days
Secondary	Cumulative incidence of asymptomatic, mild/moderate, and severe (requiring hospitalization) SARS-CoV-2 infection.		180 days
Secondary	Influenza infection	Defined as either of 1) ARI + microbiological evidence of influenza infection, 2) seroconversion of influenza between enrolment and month 6.	180 days
Secondary	An acute respiratory tract infection	Meeting the definition stated in the primary outcome. Irrespective of requiring an intervention.	180 days
Secondary	Medically attended acute respiratory tract infection	Meeting the definition stated in the primary outcome including the requirement of an intervention.	180 days
Secondary	Acute respiratory tract infection related hospital admission	Meeting the definition stated in the primary outcome including the need of hospitalization.	180 days
Secondary	Pneumonia diagnosed by a GP or medical specialist		180 days
Secondary	Functioning in daily activities	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)	180 days
Secondary	Serious adverse events and adverse events.		180 days
Secondary	Major cardiovascular events		180 days
Secondary	All cause 6-month mortality		180 days
Secondary	History of falls		180 days
Secondary	Quality of life using the EQ5D quality of life instrument	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	180 days
Secondary	Activities in daily living	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)	180 days