Reducing Health Care Workers Absenteeism in Covid-19 Pandemic Through BCG Vaccine

Study Overview
=================
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.

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.

Conditions
-----------------
COVID-19

Intervention / Treatment
-----------------
* Drug: BCG Vaccine
* Drug: Placebo


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BCG vaccine<br>Intracutaneously 0.1ml BCG vaccine, which accounts for 0.075mg of attenuated Mycobacterium bovis. | Drug: BCG Vaccine<br>* Intracutaneously 0.1ml BCG vaccine, which accounts for 0.075mg of attenuated Mycobacterium bovis<br>* Other names: Danish strain 1331;|
| Placebo Comparator: Placebo<br>Intracutaneously 0.1ml of 0.9% NaCl solution | Drug: Placebo<br>* Intracutaneously 0.1ml NaCl 0,9%<br>* Other names: NaCl 0,9%;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Health Care Workers absenteeism | Number of days of unplanned absenteeism for any reason | Maximum of 365 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the cumulative incidence of documented COVID-19 |  | Maximum of 365 days | 
| the cumulative incidence of Hospital Admission due to documented COVID-19 |  | Maximum of 365 days | 
| the number of days of unplanned absenteeism, because of documented COVID-19 |  | Maximum of 365 days | 
| the cumulative incidence of self-reported acute respiratory symptoms or fever |  | Maximum of 365 days | 
| the cumulative incidence of death due to documented COVID-19 |  | Maximum of 365 days | 
| the cumulative incidence of Intensive Care Admission due to documented COVID-19 |  | Maximum of 365 days | 
| the number of days of absenteeism, because of imposed quarantine as a result of exposure to COVID-19 | Exploratory | Maximum of 365 days | 
| the number of days of absenteeism, because of imposed quarantine as a result of having acute respiratory symptoms, fever or documented COVID-19 | Exploratory | Maximum of 365 days | 
| the number of days of unplanned absenteeism because of self-reported acute respiratory symptoms | Exploratory | Maximum of 365 days | 
| the number of days of self-reported fever (≥38 gr C) | Exploratory | Maximum of 365 days | 
| the cumulative incidence of self-reported fever (≥38 gr C) | Exploratory | Maximum of 365 days | 
| the number of days of self-reported acute respiratory symptoms | Exploratory | Maximum of 365 days | 
| the cumulative incidence of self-reported acute respiratory symptoms | Exploratory | Maximum of 365 days | 
| the cumulative incidence of death for any reason | Exploratory | Maximum of 365 days | 
| the cumulative incidence of Intensive Care Admission for any reason | Exploratory | Maximum of 365 days | 
| the cumulative incidence of Hospital Admission for any reason | Exploratory | Maximum of 365 days | 
| 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 | Exploratory | Maximum of 365 days | 
| 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 | Exploratory | 3-6 months after inclusion | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Health care workers