Clinical trial NCT04537663: Prevention Of Respiratory Tract Infection And Covid-19 Through BCG Vaccination In Vulnerable Older Adults
Official title: Bacillus Calmette-Guérin Vaccination to Prevent Serious Respiratory Tract Infection and Covid-19 in Vulnerable Elderly - an Adaptive randoMized controllEd Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Respiratory Tract Infections
Covid19
Keywords: Bacillus Calmette-Guerin
Lead sponsor: UMC Utrecht
Sponsor class: OTHER
First posted: 2020-09-03
Enrollment: 6112
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.


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

Primary outcomes:
measure: 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.
timeFrame: 180 days
Secondary outcomes:
measure: Cumulative incidence of SARS-CoV-2 infection (irrespective the presence of symptoms)
timeFrame: 180 days
measure: Cumulative incidence of asymptomatic, mild/moderate, and severe (requiring hospitalization) SARS-CoV-2 infection.
timeFrame: 180 days
measure: Influenza infection
timeFrame: 180 days
measure: An acute respiratory tract infection
timeFrame: 180 days
measure: Medically attended acute respiratory tract infection
timeFrame: 180 days
measure: Acute respiratory tract infection related hospital admission
timeFrame: 180 days
measure: Pneumonia diagnosed by a GP or medical specialist
timeFrame: 180 days
measure: Functioning in daily activities
timeFrame: 180 days
measure: Serious adverse events and adverse events.
timeFrame: 180 days
measure: Major cardiovascular events
timeFrame: 180 days
measure: All cause 6-month mortality
timeFrame: 180 days
measure: History of falls
timeFrame: 180 days
measure: Quality of life using the EQ5D quality of life instrument
timeFrame: 180 days
measure: Activities in daily living
timeFrame: 180 days
Other outcomes:
Locations:
city: Amersfoort
country: Netherlands
facility: Meander Medical Center
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Center
city: Amsterdam
country: Netherlands
facility: OLVG
city: Arnhem
country: Netherlands
facility: Rijnstate hospital
city: Breda
country: Netherlands
facility: Amphia hospital
city: Den Haag
country: Netherlands
facility: Hagahospital
city: Eindhoven
country: Netherlands
facility: Catharina hospital
city: Geleen
country: Netherlands
facility: Zuyderland Hospital
city: Groningen
country: Netherlands
facility: Martini hospital
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Nieuwegein
country: Netherlands
facility: St. Antonius hospital
city: Nijmegen
country: Netherlands
facility: Canisius-Wilhelmina Hospital
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
city: Rotterdam
country: Netherlands
facility: Ikazia Hospital
city: Rotterdam
country: Netherlands
facility: Maasstad Hospital
city: Uden
country: Netherlands
facility: Bernhoven hospital
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
Study officials:
affiliation: UMC Utrecht
name: Marc Bonten, MD, PhD.
role: PRINCIPAL_INVESTIGATOR
affiliation: Radboud University Medical Center
name: Mihai Netea, MD, PhD
role: STUDY_CHAIR
References: