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

NCT ID: NCT04537663

Last Updated: 2022-09-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 6112 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-09-07
• Study Completion Date: 2021-07-08

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.

Conditions

Respiratory Tract Infections; Covid19

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Bacille Calmette-Guérin (BCG)

Intradermal injection of BCG-Vaccine SSI \[Statens Serum Institut\]) - Danish strain 1331.

Group Type: EXPERIMENTAL

Bacille Calmette-Guérin (BCG)

Intervention Type: 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

Intradermal injection of sterile 0.9% NaCl.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Intradermal injection of sterile 0.9% NaCl.

Interventions

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).

Intervention Type: DRUG

Placebo

Intradermal injection of sterile 0.9% NaCl.

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

UMC Utrecht

OTHER

Sponsor Role: lead

Responsible Party

MJM Bonten

Prof. dr.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Marc Bonten, MD, PhD.

Role: PRINCIPAL_INVESTIGATOR

UMC Utrecht

Mihai Netea, MD, PhD

Role: STUDY_CHAIR

Radboud University Medical Center

Locations

Meander Medical Center

Amersfoort, , Netherlands

Amsterdam University Medical Center

Amsterdam, , Netherlands

OLVG

Amsterdam, , Netherlands

Rijnstate hospital

Arnhem, , Netherlands

Amphia hospital

Breda, , 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

Hagahospital

The Hague, , Netherlands

Bernhoven hospital

Uden, , Netherlands

University Medical Center Utrecht

Utrecht, , Netherlands

Countries

Netherlands

Provided Documents

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

BCG-PRIME

Identifier Type: -

Identifier Source: org_study_id