BCG Vaccination to Protect Healthcare Workers Against COVID-19 (BRACE)

BCG Vaccination to Reduce the Impact of COVID-19 in Healthcare Workers (BRACE) Trial

Phase III, two-group multicentre, randomised controlled trial in up to 10 078 healthcare workers to determine if BCG vaccination reduces the incidence and severity of COVID-19 during the 2020 pandemic.

Study Overview

• Status: Completed
• Conditions: COVID-19; Corona Virus Infection; Coronavirus Disease 2019 (COVID-19); Respiratory Illness
• Intervention / Treatment: Drug: BCG Vaccine; Drug: 0.9%NaCl

Detailed Description

Healthcare workers are at the frontline of the coronavirus disease (COVID-19) pandemic. They will be randomised to receive a single dose of BCG vaccine or 0.9% NaCl placebo. Participants will be followed-up for 12 months with notification from a Smartphone application or phone calls (up to daily when ill) and surveys to identify and detail COVID-19 infection. Additional information on severe disease will be obtained from hospital medical records and/or government databases. Blood samples will be collected prior to randomisation and at 3, 6, 9 and 12 months to determine exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Where required, swab/blood samples will be taken at illness episodes to assess SARS-CoV-2 infection.

The trial includes a pre-planned meta-analysis with data from 2834 participants recruited in the Stage 1 of this study, where participants were randomised to receive BCG or no BCG vaccine at the time of receiving influenza vaccination.

• Study Type: Interventional
• Enrollment (Actual): 6828
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2145
      • Westmead Hospital
    • Sydney, New South Wales, Australia, 2145
      • The Children's Hospital at Westmead
    • Sydney, New South Wales, Australia, 2010
      • St Vincent's Hospital, Sydney
    • Sydney, New South Wales, Australia, 2031
      • Prince of Wales Hospital
    • Sydney, New South Wales, Australia, 2145
      • Sydney Children's Hospital, Randwick
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
    • North Adelaide, South Australia, Australia, 5006
      • Women's and Children's Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3121
      • Epworth Richmond
    • Melbourne, Victoria, Australia, 3052
      • Royal Children's Hospital
    • Melbourne, Victoria, Australia, 3168
      • Monash Health- Monash Medical Centre
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • Fiona Stanley Hospital
    • Perth, Western Australia, Australia, 6009
      • Perth Children's Hospital
    • Perth, Western Australia, Australia, 6009
      • Sir Charles Gairdner Hospital
• Brazil
  • Amazonas
    • Manaus, Amazonas, Brazil, 69040-000
      • Fundação de Medicina Tropical Dr Heitor Vieira Dourado (FMT-HVD)
  • Mato Grosso Do Sul
    • Campo Grande, Mato Grosso Do Sul, Brazil, 79002-230
      • Santa Casa Hospital
    • Campo Grande, Mato Grosso Do Sul, Brazil, 79002-251
      • CASSEMS Hospital
    • Campo Grande, Mato Grosso Do Sul, Brazil, 79070-900
      • Federal University of Mato Grosso do Sul
    • Campo Grande, Mato Grosso Do Sul, Brazil, 79084-180
      • Hospital Regional de Mato Grosso do Sul
  • RJ
    • Rio de Janeiro, RJ, Brazil, 22780-195
      • Centro de Estudos da Saúde do Trabalhador e Ecologia Humana
    • Rio de Janeiro, RJ, Brazil, 22780-195
      • Centro de Referência Prof Hélio Fraga
• Netherlands
  • Alkmaar, Netherlands, 1815 JD
    • Noord West Ziekenhuis
  • Arnhem, Netherlands, 6815 AD
    • Rijnstate Hospital
  • Breda, Netherlands, 4818 CK
    • Amphia Hospital
  • Nieuwegein, Netherlands, 3435 CM
    • St Antonius hospital
  • Nijmegen, Netherlands, 6525 GA
    • Radboud UMC
  • Utrecht, Netherlands, 3584 CX
    • University hospital in Utrecht (UMCU)
• Spain
  • Santander, Spain, 39008
    • Marqués de Valdecilla University Hospital
  • Sevilla, Spain, 41009
    • University Hospital Virgen Macarena
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • University Hospital German Trias I Pujol
    • Terrassa, Barcelona, Spain, 08221
      • Mutua Terrassa Univeristy Hospital
  • Bizkaia
    • Barakaldo, Bizkaia, Spain, 48903
      • University Hospital Cruces
• United Kingdom
  • Exeter, United Kingdom, EX1 1PR
    • Travel Clinic
  • Exeter, United Kingdom, EX2 5DW
    • Royal Devon and Exeter NHS Foundation Trust
  • Devon
    • Teignmouth, Devon, United Kingdom, TQ14 8AB
      • Teign Estuary Medical Group
  • Exeter
    • Alphington, Exeter, United Kingdom, EX2 8UP
      • Ide Lane Surgery
    • St Leonards, Exeter, United Kingdom, EX1 1SB
      • St Leonard's Practice

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Over 18 years of age

• Healthcare worker

  • This is defined as anyone who works in a healthcare setting or has face to face contact with patients.
• Provide a signed and dated informed consent form
• Australian sites only: If annual influenza vaccination is available, receiving the flu vaccine is an eligibility requirement. The flu vaccine will be required a minimum of 3 days in advance of randomisation in the BRACE trial.
• Pre-randomisation blood collected

Exclusion Criteria:

• Has any BCG vaccine contraindication

  • Fever or generalised skin infection (where feasible, randomisation can be delayed until cleared)
  • Weakened resistance toward infections due to a disease in/of the immune system

  • Receiving medical treatment that affects the immune response or other immunosuppressive therapy in the last year.

    • These therapies include systemic corticosteroids (≥20 mg for ≥2 weeks), non-biological immunosuppressant (also known as 'DMARDS'), biological agents (such as monoclonal antibodies against tumour necrosis factor (TNF)-alpha).
  • People with congenital cellular immunodeficiencies, including specific deficiencies of the interferon-gamma pathway
  • People with malignancies involving bone marrow or lymphoid systems

  • People with any serious underlying illness (such as malignancy)

    • NB: People with cardiovascular disease, hypertension, diabetes, and/or chronic respiratory disease are eligible if not immunocompromised, and if they meet other eligibility criteria
  • Known or suspected HIV infection,even if they are asymptomatic or have normal immune function.
  • This is because of the risk of disseminated BCG infection
  • People with active skin disease such as eczema, dermatitis or psoriasis at or near the site of vaccination
  • A different adjacent site on the upper arm can be chosen if necessary

  • Pregnant

    • Although there is no evidence that BCG vaccination is harmful during pregnancy, it is a contra-indication to BCG vaccination. Therefore, we will exclude women who think they could be pregnant or are planning to become pregnant within the next month.
    • UK specific: Although there is no evidence that BCG vaccination is harmful during pregnancy, it is a contra-indication to BCG vaccination. Therefore, we will exclude women of childbearing potential (WOCBP) who think they could be pregnant.
    • Spain specific: If the patient is female, and of childbearing potential, she must have a negative pregnancy test at the time of inclusion and practice a reliable method of birth control for 30 days after receiving the BCG vaccination.
  • Another live vaccine administered in the month prior to randomisation

  • Require another live vaccine to be administered within the month following BCG randomisation

    • If the other live vaccine can be given on the same day, this exclusion criteria does not apply
  • Known anaphylactic reaction to any of the ingredients present in the BCG vaccine
  • Previous active TB disease
  • Currently receiving long term (more than 1 month) treatment with isoniazid, rifampicin or quinolone as these antibiotics have activity against Mycobacterium bovis
• Previous adverse reaction to BCG vaccine (significant local reaction (abscess) or suppurative lymphadenitis)
• BCG vaccine given within the last year
• Have previously had a SARS-CoV-2 positive test result (positive PCR on a respiratory sample or a positive SARS-CoV-2 diagnostic antigen test approved by the local jurisdiction's public health policy)
• Already part of this trial, recruited at a different site/hospital.
• Participation in another COVID-19 prevention trial
• Have previously received a COVID-19-specific vaccine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BCG vaccine; Participants will receive a single dose of BCG vaccine (BCG-Denmark). The adult dose of BCG vaccine is 0.1 mL injected intradermally over the distal insertion of the deltoid muscle onto the humerus (approximately one third down the upper arm).	Drug: BCG Vaccine; Freeze-dried powder: Live attenuated strain of Mycobacterium bovis (BCG), Danish strain 1331. Each 0.1 ml vaccine contains between 200000 to 800000 colony forming units. Adult dose is 0.1 ml given by intradermal injection; Other Names: Bacille Calmette-Guerin Vaccine; Bacillus Calmette-Guerin Vaccine; Statens Serum Institute BCG vaccine; Mycobacterium bovis BCG (Bacille Calmette Guérin), Danish Strain 1331; BCG Denmark
Placebo Comparator: 0.9% Saline; Participants will receive a single 0.1 mL dose of 0.9%NaCl injected intradermally over the distal insertion of the deltoid muscle onto the humerus (approximately one third down the upper arm).	Drug: 0.9%NaCl; 0.9% Sodium Chloride Injection; Other Names: 0.9% Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptomatic COVID-19 by 6 months	Number of participants with Symptomatic COVID-19 defined as; positive SARS-Cov-2 test (PCR, RAT or serology), plus; fever (using self-reported questionnaire), or; at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (using self-reported questionnaire)	Measured over the 6 months following randomisation
Severe COVID-19 incidence over 6 months	Number of participants with severe COVID-19 defined as: positive SARS-CoV-2 test (PCR, RAT or serology), PLUS; death as a consequence of COVID-19, OR; Hospitalised as a consequence of COVID-19, OR; Non-hospitalised severe disease as a consequence of COVID-19, defined as non- ambulant* for ≥ 3 consecutive days unable to work** for ≥ 3 consecutive days (*) "pretty much confined to bed (meaning finding it very difficult to do any normal daily activities". (**) "I do not feel physically well enough to go to work"	Measured over the 6 months following randomisation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptomatic COVID-19 by 12 months	Number of participants symptomatic COVID-19 disease defined as; positive SARS-Cov-2 test (PCR, RAT or serology), plus; fever (using self-reported questionnaire), or; at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (using self-reported questionnaire)	Measured over the 12 months following randomisation
Severe COVID-19 incidence over 12 months	Number of participants with severe COVID-19 defined as: positive SARS-CoV-2 test (PCR, RAT or serology), PLUS; death as a consequence of COVID-19, OR; Hospitalised as a consequence of COVID-19, OR; Non-hospitalised severe disease as a consequence of COVID-19, defined as non- ambulant* for ≥ 3 consecutive days unable to work** for ≥ 3 consecutive days (*) "pretty much confined to bed (meaning finding it very difficult to do any normal daily activities". (**) "I do not feel physically well enough to go to work"	Measured over the 12 months following randomisation
Time to first symptom of COVID-19	Participants who had either a symptomatic or severe COVID-19 episode will have time to first symptom of COVID-19 calculated as: [Date of any symptom onset for the first symptomatic or severe COVID-19 episode - Date of randomisation] Participants who have not had a symptomatic or severe COVID-19 episode will have time calculated as: [Earliest censoring date - date of randomisation]	Measured over the 6 and 12 months following randomisation
Number of Episodes of COVID-19	The total number of symptomatic or severe COVID-19 episodes (refer to outcome 3 and 4 for definitions)	Measured over the 6 and 12 months following randomisation
Asymptomatic SARS-CoV-2 infection	Number of participants with asymptomatic SARS-CoV-2 infection defined as; Evidence of SARS-CoV-2 infection (by seroconversion); Absence of respiratory illness (defined by trigger or non-trigger symptoms)(using self- reported questionnaire); No evidence of exposure prior to randomisation	Measured over the 6 and 12 months following randomisation
Work absenteeism due to COVID-19	Number of days (using self-reported questionnaire) unable to work (excludes quarantine/workplace restrictions) due to COVID-19 defined as; positive SARS-Cov-2 test (PCR, RAT or serology), plus; fever (using self-reported questionnaire), or; at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (using self-reported questionnaire)	Measured within 6 and 12 months following randomisation
Bed confinement due to COVID-19	Number of days confined to bed (using self-reported questionnaire) due to COVID-19 disease defined as; positive SARS-Cov-2 test (PCR, RAT or serology), plus; fever (using self-reported questionnaire), or; at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (using self-reported questionnaire)	Measured over 6 and 12 months following randomisation
Symptom duration of COVID-19	Number of days with symptoms in any episode of illness that meets the case definition for COVID-19 disease: positive SARS-Cov-2 test (PCR, RAT or serology), plus; fever (using self-reported questionnaire), or; at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (using self-reported questionnaire)	Measured over 6 and12 months following randomisation
Pneumonia due to COVID-19	Number of pneumonia cases (using self-reported questionnaire and/or medical/hospital records) due to COVID-19	Measured over the 6 and 12 months following randomisation
Oxygen therapy due to COVID-19	Need for oxygen therapy (using self-reported questionnaire and/or medical/hospital records) due to COVID-19	Measured over the 6 and12 months following randomisation
Critical care admissions due to COVID-19	Number of admission to critical care (using self-reported questionnaire and/or medical/hospital records) due to COVID-19	Measured over the 6 and 12 months following randomisation
Mechanical ventilation due to COVID-19	Number of participants needing mechanical ventilation (using self-reported questionnaire and/or medical/hospital records)	Measured over the 12 months following randomisation
Hospitalisation duration with COVID-19	Number of days of hospitalisation due to COVID-19 (using self-reported questionnaire and/or medical/hospital records).	Measured over the 6 and 12 months following randomisation
Mortality due to COVID-19	Number of deaths due to COVID-19	Measured over the 6 and 12 months following randomisation
Fever or respiratory illness	Respiratory illness using self-reported questionnaire defined as: at least one sign or symptom of respiratory disease including cough, sore throat, shortness of breath, respiratory distress/failure, or runny/blocked nose (in combination with another respiratory symptom or fever).	Measured over the 12 months following randomisation
Severe fever or respiratory illness	Severe fever or respiratory illness using self-reported questionnaire defined as: Death, or; Hospitalised, or; Non-hospitalised severe disease, defined as non-ambulant1 for ≥ 3 consecutive days or unable to work2 for ≥ 3 consecutive days	Measured over the 12 months following randomisation
Episodes of fever or respiratory illness	Respiratory illness using self-reported questionnaire defined as: at least one sign or symptom of respiratory disease including cough, sore throat, shortness of breath, respiratory distress/failure, or runny/blocked nose (in combination with another respiratory symptom or fever).	Measured over the 12 months following randomisation
Work absenteeism due to fever or respiratory illness	Number of days (using self-reported questionnaire) unable to work (excludes quarantine/workplace restrictions) due to fever or respiratory illness defined as; fever (using self-reported questionnaire), or; at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure, runny/blocked nose (using self-reported questionnaire)	Measured over the 12 months following randomisation
Bed confinement due to fever or respiratory illness	Number of days confined to bed (using self-reported questionnaire) due to fever or respiratory illness defined as; fever (using self-reported questionnaire), or; at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure, runny/blocked nose (using self-reported questionnaire)	Measured over the 12 months following randomisation
Symptom duration of fever or respiratory illness	Number of days with symptoms in any episode of illness that meets the case definition for fever or respiratory illness: fever (using self-reported questionnaire), or; at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure, runny/blocked nose (using self-reported questionnaire)	Measured over the 12 months following randomisation
Pneumonia within a febrile or respiratory illness	Number of pneumonia cases(using self-reported questionnaire and/or medical/hospital records)	Measured over the 12 months following randomisation
Oxygen therapy for a febrile or respiratory illness	Need for oxygen therapy (using self-reported questionnaire and/or medical/hospital records)	Measured over the 12 months following randomisation
Critical care admissions for a febrile or respiratory illness	Number of admission to critical care (using self-reported questionnaire and/or medical/hospital records)	Measured over the 12 months following randomisation
Mechanical ventilation for a febrile or respiratory illness	Number of participants needing mechanical ventilation (using self-reported questionnaire and/or medical/hospital records)	Measured over the 12 months following randomisation
Mortality as a consequence of an episode of fever or respiratory illness	Number of deaths	Measured over the 12 months following randomisation
Hospitalisation duration for a febrile or respiratory illness	Number of days of hospitalisation due to fever or respiratory illness (using self-reported questionnaire, medical/hospital records)	Measured within 6 and 12 months following randomisation
Unplanned work absenteeism for an acute illness or hospitalisation	Number of days of unplanned absenteeism for any reason (using self-reported questionnaire)	Measured over the 6 and 12 months following randomisation
Local and systemic adverse events to BCG vaccination in healthcare workers	Adverse events (AEs), over the 3 months following randomisation, by type, severity (graded using toxicity grading scale), relationship to intervention of adverse events (AEs) of interest.	Measured over the 3 months following randomisation
Serious Adverse Events (SAEs) to BCG vaccination in healthcare workers	SAEs over the 3 months following randomisation, by type, severity (graded using toxicity grading scale), relationship to intervention.	Measured over the 3 months following randomisation

Collaborators and Investigators

• Sponsor: Murdoch Childrens Research Institute
• Collaborators: Bill and Melinda Gates Foundation; Royal Children's Hospital
• Investigators: Principal Investigator: Prof Nigel Curtis, Murdoch Children'S Research Institute

Publications and helpful links

General Publications

• Pittet LF, Messina NL, Gardiner K, Orsini F, Abruzzo V, Bannister S, Bonten M, Campbell JL, Croda J, Dalcolmo M, Elia S, Germano S, Goodall C, Gwee A, Jamieson T, Jardim B, Kollmann TR, Guimaraes Lacerda MV, Lee KJ, Legge D, Lucas M, Lynn DJ, McDonald E, Manning L, Munns CF, Perrett KP, Prat Aymerich C, Richmond P, Shann F, Sudbury E, Villanueva P, Wood NJ, Lieschke K, Subbarao K, Davidson A, Curtis N; BRACE trial Consortium Group. BCG vaccination to reduce the impact of COVID-19 in healthcare workers: Protocol for a randomised controlled trial (BRACE trial). BMJ Open. 2021 Oct 28;11(10):e052101. doi: 10.1136/bmjopen-2021-052101.
• Crisan-Dabija R, Grigorescu C, Pavel CA, Artene B, Popa IV, Cernomaz A, Burlacu A. Tuberculosis and COVID-19: Lessons from the Past Viral Outbreaks and Possible Future Outcomes. Can Respir J. 2020 Sep 5;2020:1401053. doi: 10.1155/2020/1401053. eCollection 2020.

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2020
• Primary Completion (Actual): November 10, 2021
• Study Completion (Actual): May 27, 2022

Study Registration Dates

• First Submitted: March 25, 2020
• First Submitted That Met QC Criteria: March 27, 2020
• First Posted (Actual): March 31, 2020

Study Record Updates

• Last Update Posted (Actual): September 1, 2022
• Last Update Submitted That Met QC Criteria: August 29, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Coronavirus Infections; Physiological Effects of Drugs; Immunologic Factors; Adjuvants, Immunologic; Vaccines; BCG Vaccine
• Other Study ID Numbers: 62586; U1111-1256-4104 (Registry Identifier: The Universal Trial Number (UTN)); INV-017302 (Other Grant/Funding Number: BILL & MELINDA GATES foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Under the terms of the funding agreement with the Bill and Melinda Gates foundation, the BRACE trial has a data sharing agreement in place.

An anonymised Individual Participant Data (IPD) dataset and a data dictionary will be provided to Vivli (https://vivli.org/) under the terms of the agreements with the Bill and Melinda Gates foundation grant and Vivli.

After database lock, the following may be made available long-term for use by future researchers from a recognised research institution whose proposed use of the data has been ethically reviewed and approved by an independent committee and who accept MCRI's conditions, under a collaborator agreement, for accessing:

• Individual participant data that underlie the results reported in our articles after deidentification (text, tables, figures and appendices)
• Study protocol, Statistical Analysis Plan, PICF

• IPD Sharing Time Frame: After database lock, a 12-month embargo period will be in place, to allow adequate time for analyses and publication outputs. Data transfer to Vivli should occur during the embargo period.

IPD Sharing Access Criteria

Researchers from a recognised research institution can approach MCRI for access of data.

The researcher will need to provide evidence that the proposed use of the data has been ethically reviewed and approved by an Institutional Review Board (IRB)/ Human Research Ethics Committee(HREC), and accept MCRI's conditions, under a collaborator agreement.

• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No