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

• ClinicalTrials.gov Identifier: NCT04328441
• Recruitment Status: Active, not recruiting
• First Posted: March 31, 2020
• Last Update Posted: August 19, 2020
• Sponsor: UMC Utrecht
• Collaborator: Radboud University
• Information provided by (Responsible Party): MJM Bonten, UMC Utrecht

Tracking Information

• First Submitted Date: March 27, 2020
• First Posted Date: March 31, 2020
• Last Update Posted Date: August 19, 2020
• Actual Study Start Date: March 25, 2020
• Estimated Primary Completion Date: March 31, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 15, 2020)

Health Care Workers absenteeism [ Time Frame: Maximum of 365 days ]

Number of days of unplanned absenteeism for any reason

Original Primary Outcome Measures (submitted: March 27, 2020)

Health Care Workers absenteeism [ Time Frame: Maximum of 6 months ]

Number of days of unplanned absenteeism for any reason

Current Secondary Outcome Measures (submitted: August 15, 2020)

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

Original Secondary Outcome Measures (submitted: March 27, 2020)

• The cumulative incidence of documented SARS-CoV-2 infection [ Time Frame: Maximum of 6 months ]
• The number of days of unplanned absenteeism, because of documented SARS-CoV-2 infection [ Time Frame: Maximum of 6 months ]
• The number of days of absenteeism, because of imposed quarantine as a result of exposure to SARS-CoV-2 infection [ Time Frame: Maximum of 6 months ]
• The number of days of absenteeism, because of imposed quarantine as a result of having acute respiratory symptoms, fever or documented SARS-CoV-2 infection [ Time Frame: Maximum of 6 months ]
• the number of days of unplanned absenteeism because of self-reported acute respiratory symptoms [ Time Frame: Maximum of 6 months ]
• the number of days of self-reported fever (≥38 gr C) [ Time Frame: Maximum of 6 months ]
• the number of days of self-reported acute respiratory symptoms [ Time Frame: Maximum of 6 months ]
• The cumulative incidence of self-reported acute respiratory symptoms [ Time Frame: Maximum of 6 months ]
• the cumulative incidence of death for any reason [ Time Frame: Maximum of 6 months ]
• The cumulative incidence of death due to documented SARS-CoV-2 infection [ Time Frame: Maximum of 6 months ]
• the cumulative incidence of Intensive Care Admission for any reason [ Time Frame: Maximum of 6 months ]
• The cumulative incidence of Intensive Care Admission due to documented SARS-CoV-2 infection [ Time Frame: Maximum of 6 months ]
• the cumulative incidence of Hospital Admission for any reason [ Time Frame: Maximum of 6 months ]
• The cumulative incidence of Hospital Admission due to documented SARS-CoV-2 infection [ Time Frame: Maximum of 6 months ]
• The incidence and magnitude of SARS-CoV-2 antibodies at the end of the study period [ Time Frame: Maximum of 6 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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.

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.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Unblinded are the pharmacist and the research nurse that administers the study medication. These persons are not involved in the further conduction of the trial or in the assessment of outcomes.

Primary Purpose: Prevention

• Condition: COVID-19

Intervention

• Drug: BCG Vaccine
  Intracutaneously 0.1ml BCG vaccine, which accounts for 0.075mg of attenuated Mycobacterium bovis
  Other Name: Danish strain 1331
• Drug: Placebo
  Intracutaneously 0.1ml NaCl 0,9%
  Other Name: NaCl 0,9%

Study Arms

• Experimental: BCG vaccine
  Intracutaneously 0.1ml BCG vaccine, which accounts for 0.075mg of attenuated Mycobacterium bovis.
  Intervention: Drug: BCG Vaccine
• Placebo Comparator: Placebo
  Intracutaneously 0.1ml of 0.9% NaCl solution
  Intervention: Drug: Placebo

• Publications *: 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-Guérin 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. Erratum in: Trials. 2020 Jun 22;21(1):555.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: March 31, 2020): 1500
• Original Estimated Enrollment (submitted: March 27, 2020): 1000
• Estimated Study Completion Date: April 30, 2021
• Estimated Primary Completion Date: March 31, 2021 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT04328441
• Other Study ID Numbers: NL73249.041.20
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: The results of this study will be disclosed unreservedly at the end of the study.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Supporting Materials: Analytic Code

Time Frame

The content of the study protocol is published. The statistical analysis plan is attached. The informed consent form (in Dutch) could be obtained by sending a mail to one of the contact persons.

The clinical study report and analytic code could be obtained by sending a mail to one of the contact persons after publication of the study in a peer-reviewed journal.

• Responsible Party: MJM Bonten, UMC Utrecht
• Study Sponsor: UMC Utrecht
• Collaborators: Radboud University

Investigators

• Principal Investigator: Marc Bonten, MD, PhD; UMC Utrecht

• PRS Account: UMC Utrecht
• Verification Date: August 2020