Clinical trial NCT04328441: Reducing Health Care Workers Absenteeism in Covid-19 Pandemic Through BCG Vaccine
Official title: Reducing Health Care Workers Absenteeism in COVID-19 Pandemic by Enhanced Trained Immune Responses Through Bacillus Calmette-Guérin Vaccination, a Randomized Controlled Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: COVID-19
Keywords: Health care workers
Lead sponsor: UMC Utrecht
Sponsor class: OTHER
Collaborators: name: Radboud University Medical Center
First posted: 2020-03-31
Enrollment: 1511
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Rationale: Covid-19 spreads rapidly throughout the world. A large epidemic in the Netherlands would seriously challenge the available hospital capacity, and this would be augmented by absenteeism of healthcare workers (HCW). Strategies to prevent absenteeism of HCW are, therefore, desperately needed to safeguard continuous patient care. Bacille Calmette-Guérin (BCG) is a vaccine against tuberculosis, with protective non-specific effects against other respiratory tract infections in in vitro and in vivo studies, and reported significant reductions in morbidity and mortality. The hypothesis is that BCG vaccination can reduce HCW absenteeism during the epidemic phase of Covid-19.

Objective: Primary objective: To reduce absenteeism among HCW with direct patient contacts during the epidemic phase of Covid-19. Secondary objective: To reduce hospital admission, ICU admission or death in HCW with direct patient contacts during the epidemic phase of Covid-19.

Study design: A placebo-controlled adaptive multi-centre randomized controlled trial.

Study population: HCW with direct patient contacts among which nurses and physicians working at emergency rooms and wards where Covid-19-infected patients are treated.

Intervention: Participants will be randomized between intracutaneous administration of BCG vaccine or placebo in a 1:1 ratio.

Main study parameters/endpoints: Primary endpoint: number of days of (unplanned) absenteeism for any reason. Secondary endpoints include the number of days of (unplanned) absenteeism because of documented Covid-19 infection, and the cumulative incidence of hospital admission, Intensive Care Admission, and death.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Based on previous experience and randomized controlled trials in adult and elderly individuals, the risks of BCG vaccination are considered low. The objective of this trial is to evaluate the beneficial effects of BCG vaccination through a lower work absenteeism rate of HCW and/or a mitigated clinical course of Covid-19 infection. The primary endpoint and the adaptive design with frequent interim analyses facilitate maximum efficiency of the trial, so that results can inform policy making during the ongoing epidemic.

Detailed description: Since the beginning of 2020, SARS-CoV-2 spread rapidly throughout China and the rest of the world, with on 27 February 2020 the first detected case in the Netherlands.

According to the WHO, Health-care workers (HCW) face an elevated risk of exposure to - and infection of Covid-19.

Bacillus Calmette-Guérin (BCG) was developed as a vaccine against tuberculosis, but studies have shown its ability to induce potent protection against other infectious diseases: the so called non-specific effects (NSEs). A favorable in vitro or in vivo effect has been observed in studies for distinct viral pathogens, e.g. respiratory syncytial virus, yellow fever, herpes simplex virus; human papilloma virus.

Based on the capacity of BCG to reduce the incidence of respiratory tract infections in children, to exert antiviral effects in experimental models; and to reduce viremia in an experimental human model of viral infection, the hypothesis is that BCG vaccination induces (partial) protection against susceptibility to and/or severity of Covid-19 infection. This study evaluates the efficacy of BCG to improve the clinical course of Covid-19 infection and to prevent absenteeism in order to safeguard continuous patient care.

This randomized controlled trial has been designed as a pragmatic study with a highly feasible primary endpoint, which is unplanned absenteeism, that can be continuously measured on a bi-weekly basis). This allows for the most rapid identification of a beneficial outcome that would allow other HCWs to also benefit from the intervention if and as soon as it has been demonstrated to be effective.

Eligibility criteria: Inclusion Criteria:

* Adult (≥18 years)
* Male or female
* Hospital personnel (expected to) taking care for patients with SARS CoV-2 infection

Exclusion Criteria:

* Known allergy to (components of) the BCG vaccine or serious adverse events to prior BCG administration
* Known active or latent Mycobacterium tuberculosis or with another mycobacterial species. A history with- or a suspicion of M. tuberculosis infection.
* Fever (\>38 C) within the past 24 hours
* Pregnancy
* Suspicion of active viral or bacterial infection
* Vaccination in the past 4 weeks or expected vaccination during the study period, independent of the type of vaccination.
* Severely immunocompromised subjects. This exclusion category comprises: a) subjects with known infection by the human immunodeficiency virus (HIV-1); b) neutropenic subjects with less than 500 neutrophils/mm3; c) subjects with solid organ transplantation; d) subjects with bone marrow transplantation; e) subjects under chemotherapy; f) subjects with primary immunodeficiency; g) severe lymphopenia with less than 400 lymphocytes/mm3; h) treatment with any anti-cytokine therapies. i) treatment with oral or intravenous steroids defined as daily doses of 10mg prednisone or equivalent for longer than 3 months, or probable use of oral or intravenous steroids in the following four weeks
* Active solid or non-solid malignancy or lymphoma within the prior two years
* Direct involvement in the design or the execution of the BCG-CORONA study
* Expected absence from work of ≥4 of the following 12 weeks due to any reason (holidays, maternity leave, retirement, planned surgery etc)
* Employed to the hospital \< 22 hours per week
* Not in possession of a smartphone

Primary outcomes:
measure: Health Care Workers absenteeism
timeFrame: Maximum of 365 days
Secondary outcomes:
measure: the cumulative incidence of documented COVID-19
timeFrame: Maximum of 365 days
measure: the cumulative incidence of Hospital Admission due to documented COVID-19
timeFrame: Maximum of 365 days
measure: the number of days of unplanned absenteeism, because of documented COVID-19
timeFrame: Maximum of 365 days
measure: the cumulative incidence of self-reported acute respiratory symptoms or fever
timeFrame: Maximum of 365 days
measure: the cumulative incidence of death due to documented COVID-19
timeFrame: Maximum of 365 days
measure: the cumulative incidence of Intensive Care Admission due to documented COVID-19
timeFrame: Maximum of 365 days
measure: the number of days of absenteeism, because of imposed quarantine as a result of exposure to COVID-19
timeFrame: Maximum of 365 days
measure: the number of days of absenteeism, because of imposed quarantine as a result of having acute respiratory symptoms, fever or documented COVID-19
timeFrame: Maximum of 365 days
measure: the number of days of unplanned absenteeism because of self-reported acute respiratory symptoms
timeFrame: Maximum of 365 days
measure: the number of days of self-reported fever (≥38 gr C)
timeFrame: Maximum of 365 days
measure: the cumulative incidence of self-reported fever (≥38 gr C)
timeFrame: Maximum of 365 days
measure: the number of days of self-reported acute respiratory symptoms
timeFrame: Maximum of 365 days
measure: the cumulative incidence of self-reported acute respiratory symptoms
timeFrame: Maximum of 365 days
measure: the cumulative incidence of death for any reason
timeFrame: Maximum of 365 days
measure: the cumulative incidence of Intensive Care Admission for any reason
timeFrame: Maximum of 365 days
measure: the cumulative incidence of Hospital Admission for any reason
timeFrame: Maximum of 365 days
measure: the cumulative incidence and magnitude of plasma/serum antibodies (IgA,M,G) and SARS-CoV-2-specific antibodies at 12 weeks after vaccination and at the end of the study period
timeFrame: Maximum of 365 days
measure: the cumulative incidence and magnitude of plasma/serum antibodies (IgA,M,G) and SARS-CoV-2-specific antibodies at 12 weeks after vaccination and at the end of the study period
timeFrame: 3-6 months after inclusion
Other outcomes:
Locations:
city: Den Bosch
country: Netherlands
facility: Jeroen Bosch ziekenhuis
state: Brabant
city: Nijmegen
country: Netherlands
facility: Canisius Wilhelmina Ziekenhuis
state: Gelderland
city: Nijmegen
country: Netherlands
facility: Radboud UMC
state: Gelderland
city: Nijmegen
country: Netherlands
facility: Sint Maartenskliniek
state: Gelderland
city: Alkmaar
country: Netherlands
facility: Noordwest Ziekenhuisgroep locatie Alkmaar
state: Noord Holland
city: Den Haag
country: Netherlands
facility: Hagaziekenhuis
state: Zuid-Holland
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
state: Zuid-Holland
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
state: Zuid-Holland
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
Study officials:
affiliation: UMC Utrecht
name: Marc Bonten, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ten Doesschate T, Moorlag SJCFM, van der Vaart TW, Taks E, Debisarun P, Ten Oever J, Bleeker-Rovers CP, Verhagen PB, Lalmohamed A, Ter Heine R, van Crevel R, van de Wijgert J, Janssen AB, Bonten MJ, van Werkhoven CH, Netea MG; BCG-CORONA study team#. Two Randomized Controlled Trials of Bacillus Calmette-Guerin Vaccination to reduce absenteeism among health care workers and hospital admission by elderly persons during the COVID-19 pandemic: A structured summary of the study protocols for two randomised controlled trials. Trials. 2020 Jun 5;21(1):481. doi: 10.1186/s13063-020-04389-w.