BCG Vaccination to Protect Healthcare Workers Against COVID-19

NCT04327206 | Completed Phase 3

• 3 other identifiers: 62586U1111-1256-4104INV-017302
• Study Type: interventional
• Target: 6,828
• Locations: 5 countries
• Sites: 36

Brief Summary

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.

Conditions

Coronavirus Disease 2019 (COVID-19); Respiratory Illness; Corona Virus Infection; COVID-19

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (29)

• Symptomatic COVID-19 by 12 months

  Measured over the 12 months following randomisation

• Severe COVID-19 incidence over 12 months

  Measured over the 12 months following randomisation

• Time to first symptom of COVID-19

  Measured over the 6 and 12 months following randomisation

• Number of Episodes of COVID-19

  Measured over the 6 and 12 months following randomisation

• Asymptomatic SARS-CoV-2 infection

  Measured over the 6 and 12 months following randomisation

Study Arms (2)

BCG vaccine

EXPERIMENTAL

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

0.9% Saline

PLACEBO COMPARATOR

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

Interventions

BCG Vaccine DRUG

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

Also known as: Bacille Calmette-Guerin Vaccine, Bacillus Calmette-Guerin Vaccine, Statens Serum Institute BCG vaccine, Mycobacterium bovis BCG (Bacille Calmette Guérin), Danish Strain 1331, BCG Denmark

BCG vaccine

0.9%NaCl DRUG

0.9% Sodium Chloride Injection

Also known as: 0.9% Saline

0.9% Saline

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Murdoch Childrens Research Institute: lead
• Royal Children's Hospital: collaborator
• Bill and Melinda Gates Foundation: collaborator

Study Sites (36)

St Vincent's Hospital, Sydney

Sydney, New South Wales, 2010, Australia

Location

Prince of Wales Hospital

Sydney, New South Wales, 2031, Australia

Location

Sydney Children's Hospital, Randwick

Sydney, New South Wales, 2145, Australia

Location

The Children's Hospital at Westmead

Sydney, New South Wales, 2145, Australia

Location

Westmead Hospital

Sydney, New South Wales, 2145, Australia

Location

Royal Adelaide Hospital

Adelaide, South Australia, 5000, Australia

Location

Women's and Children's Hospital

North Adelaide, South Australia, 5006, Australia

Location

Royal Children's Hospital

Melbourne, Victoria, 3052, Australia

Location

Epworth Richmond

Melbourne, Victoria, 3121, Australia

Location

Monash Health- Monash Medical Centre

Melbourne, Victoria, 3168, Australia

Location

Fiona Stanley Hospital

Murdoch, Western Australia, 6150, Australia

Location

Perth Children's Hospital

Perth, Western Australia, 6009, Australia

Location

Sir Charles Gairdner Hospital

Perth, Western Australia, 6009, Australia

Location

Fundação de Medicina Tropical Dr Heitor Vieira Dourado (FMT-HVD)

Manaus, Amazonas, 69040-000, Brazil

Location

Santa Casa Hospital

Campo Grande, Mato Grosso do Sul, 79002-230, Brazil

Location

CASSEMS Hospital

Campo Grande, Mato Grosso do Sul, 79002-251, Brazil

Location

Federal University of Mato Grosso do Sul

Campo Grande, Mato Grosso do Sul, 79070-900, Brazil

Location

Hospital Regional de Mato Grosso do Sul

Campo Grande, Mato Grosso do Sul, 79084-180, Brazil

Location

Centro de Estudos da Saúde do Trabalhador e Ecologia Humana

Rio de Janeiro, Rio de Janeiro, 22780-195, Brazil

Location

Centro de Referência Prof Hélio Fraga

Rio de Janeiro, Rio de Janeiro, 22780-195, Brazil

Location

Noord West Ziekenhuis

Alkmaar, 1815 JD, Netherlands

Location

Rijnstate Hospital

Arnhem, 6815 AD, Netherlands

Location

Amphia Hospital

Breda, 4818 CK, Netherlands

Location

St Antonius Hospital

Nieuwegein, 3435 CM, Netherlands

Location

Radboud UMC

Nijmegen, 6525 GA, Netherlands

Location

University hospital in Utrecht (UMCU)

Utrecht, 3584 CX, Netherlands

Location

University Hospital German Trias I Pujol

Badalona, Barcelona, 08916, Spain

Location

Mutua Terrassa Univeristy Hospital

Terrassa, Barcelona, 08221, Spain

Location

University Hospital Cruces

Barakaldo, Bizkaia, 48903, Spain

Location

Marqués de Valdecilla University Hospital

Santander, 39008, Spain

Location

University Hospital Virgen Macarena

Seville, 41009, Spain

Location

Teign Estuary Medical Group

Teignmouth, Devon, TQ14 8AB, United Kingdom

Location

Ide Lane Surgery

Alphington, Exeter, EX2 8UP, United Kingdom

Location

Travel Clinic

Exeter, Exeter, EX1 1PR, United Kingdom

Location

St Leonard's Practice

St Leonards, Exeter, EX1 1SB, United Kingdom

Location

Royal Devon and Exeter NHS Foundation Trust

Exeter, EX2 5DW, United Kingdom

Location

Related Publications (6)

• Messina NL, Pittet LF, McDonald E, Moore C, Barry S, Bonten M, Byrne A, Campbell J, Croda J, Croda MG, Dalcolmo M, de Almeida E Val FF, de Oliveira RD, Dos Santos G, Douglas MW, Gardiner K, Gwee A, Jardim BA, Kollmann T, Lacerda MV, Lucas M, Lynn DJ, Manning L, Marshall H, O'Connell A, Perrett KP, Post JJ, Prat-Aymerich C, Rocha JL, Rodriguez-Bano J, Wadia U, Warris A, Davidson A, Curtis N; BRACE Trial Consortium Group. BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial. J Infect. 2024 Oct;89(4):106245. doi: 10.1016/j.jinf.2024.106245. Epub 2024 Aug 8.

  PMID: 39127450 DERIVED

• Pittet LF, Messina NL, McDonald E, Orsini F, Barry S, Bonten M, Campbell J, Croda J, Croda MG, Dalcolmo M, Gardiner K, Gwee A, Jardim B, Lacerda MVG, Lucas M, Lynn DJ, Manning L, Perrett KP, Post JJ, Prat-Aymerich C, Richmond PC, Rocha JL, Rodriguez-Bano J, Warris A, Wood NJ, Davidson A, Curtis N; BRACE Trial Consortium Group. Bacille Calmette-Guerin vaccination to prevent febrile and respiratory illness in adults (BRACE): secondary outcomes of a randomised controlled phase 3 trial. EClinicalMedicine. 2024 May 13;72:102616. doi: 10.1016/j.eclinm.2024.102616. eCollection 2024 Jun.

  PMID: 38774675 DERIVED

• Pittet LF, Moore CL, McDonald E, Barry S, Bonten M, Campbell J, Croda J, Dalcolmo M, Davidson A, Douglas MW, Gardiner K, Gwee A, Jardim B, Lacerda MVG, Lucas M, Lynn DJ, Manning L, de Oliveira RD, Perrett KP, Prat-Aymerich C, Richmond PC, Rocha JL, Rodriguez-Bano J, Warris A, Wood NJ, Messina NL, Curtis N; BRACE Trial Consortium Group. Bacillus Calmette-Guerin vaccination for protection against recurrent herpes labialis: a nested randomised controlled trial. EClinicalMedicine. 2023 Sep 11;64:102203. doi: 10.1016/j.eclinm.2023.102203. eCollection 2023 Oct.

  PMID: 37719417 DERIVED

• Pittet LF, Messina NL, Orsini F, Moore CL, Abruzzo V, Barry S, Bonnici R, Bonten M, Campbell J, Croda J, Dalcolmo M, Gardiner K, Gell G, Germano S, Gomes-Silva A, Goodall C, Gwee A, Jamieson T, Jardim B, Kollmann TR, Lacerda MVG, Lee KJ, Lucas M, Lynn DJ, Manning L, Marshall HS, McDonald E, Munns CF, Nicholson S, O'Connell A, de Oliveira RD, Perlen S, Perrett KP, Prat-Aymerich C, Richmond PC, Rodriguez-Bano J, Dos Santos G, da Silva PV, Teo JW, Villanueva P, Warris A, Wood NJ, Davidson A, Curtis N; BRACE Trial Consortium Group. Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers. N Engl J Med. 2023 Apr 27;388(17):1582-1596. doi: 10.1056/NEJMoa2212616.

  PMID: 37099341 DERIVED

• 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.

  PMID: 34711598 DERIVED

• 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.

  PMID: 32934758 DERIVED

MeSH Terms

Conditions

COVID-19; Coronavirus Infections

Interventions

BCG Vaccine; Sodium Chloride; Saline Solution

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Tuberculosis Vaccines; Bacterial Vaccines; Vaccines; Biological Products; Complex Mixtures; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Prof Nigel Curtis

  Murdoch Childrens Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: The control group will receive a placebo of 0.9% sodium chloride (NaCl). Members of the research team doing the follow-up of participants and analysis will be blinded to the group allocation (by the removal of this variable and all other variables related to BCG from the dataset) until the formal detailed statistical analysis plan is confirmed and signed by all investigators and all data cleaning/preparation is complete.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Phase III, two group, multicentre, randomised controlled trial

Study Record Dates

• First Submitted: March 25, 2020
• First Posted: March 31, 2020
• Study Start: March 30, 2020
• Primary Completion: November 10, 2021
• Study Completion: May 27, 2022
• Last Updated: September 19, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• 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.
• 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.

Locations

BR (7); NL (6); ES (5); AU (13); GB (5)