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

NCT04537663 | Completed Phase 4 DMC

• 1 other identifier: BCG-PRIME
• Study Type: interventional
• Target: 6,112
• Locations: 1 country
• Sites: 20

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

Keywords

Bacillus Calmette-Guerin

Outcome Measures

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.

  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 Outcomes (14)

• Cumulative incidence of SARS-CoV-2 infection (irrespective the presence of symptoms)

  180 days

• Cumulative incidence of asymptomatic, mild/moderate, and severe (requiring hospitalization) SARS-CoV-2 infection.

  180 days

• Influenza infection

  180 days

• An acute respiratory tract infection

  180 days

• Medically attended acute respiratory tract infection

  180 days

Study Arms (2)

Bacille Calmette-Guérin (BCG)

EXPERIMENTAL

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

Drug: Bacille Calmette-Guérin (BCG)

Placebo

PLACEBO COMPARATOR

Intradermal injection of sterile 0.9% NaCl.

Drug: Placebo

Interventions

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).

Bacille Calmette-Guérin (BCG)

Placebo DRUG

Intradermal injection of sterile 0.9% NaCl.

Placebo

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Fever (\>38 ºC) within the past 24 hours
• Vaccination with live vaccine in the past four weeks or planned vaccination with live vaccine during the next four weeks
• 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
• 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

Sponsors & Collaborators

• UMC Utrecht: lead

Study Sites (20)

Meander Medical Center

Amersfoort, Netherlands

Location

Amsterdam University Medical Center

Amsterdam, Netherlands

Location

OLVG

Amsterdam, Netherlands

Location

Rijnstate hospital

Arnhem, Netherlands

Location

Amphia hospital

Breda, Netherlands

Location

Catharina hospital

Eindhoven, Netherlands

Location

Zuyderland Hospital

Geleen, Netherlands

Location

Martini hospital

Groningen, Netherlands

Location

University Medical Center Groningen

Groningen, Netherlands

Location

Leiden University Medical Center

Leiden, Netherlands

Location

Maastricht University Medical Center

Maastricht, Netherlands

Location

St. Antonius hospital

Nieuwegein, Netherlands

Location

Canisius-Wilhelmina Hospital

Nijmegen, Netherlands

Location

Radboud University Medical Center

Nijmegen, Netherlands

Location

Erasmus Medical Center

Rotterdam, Netherlands

Location

Ikazia Hospital

Rotterdam, Netherlands

Location

Maasstad Hospital

Rotterdam, Netherlands

Location

Hagahospital

The Hague, Netherlands

Location

Bernhoven hospital

Uden, Netherlands

Location

University Medical Center Utrecht

Utrecht, Netherlands

Location

MeSH Terms

Conditions

Respiratory Tract Infections; COVID-19

Condition Hierarchy (Ancestors)

Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases

Study Officials

• Marc Bonten, MD, PhD.

  UMC Utrecht

  PRINCIPAL INVESTIGATOR

• Mihai Netea, MD, PhD

  Radboud University Medical Center

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Placebo consists of intradermal injection of sterile 0.9% NaCl.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. dr.

Study Record Dates

• First Submitted: August 28, 2020
• First Posted: September 3, 2020
• Study Start: September 7, 2020
• Primary Completion: July 8, 2021
• Study Completion: July 8, 2021
• Last Updated: September 23, 2022

Record last verified: 2022-09

Locations

NL (20)