BCG vaccination to Reduce the impact of COVID-19 in healthcare workers following Coronavirus Exposure (BRACE) Trial
Latest Information Update: 11 Sep 2023
At a glance
- Drugs BCG vaccine (Primary)
- Indications COVID 2019 infections
- Focus Adverse reactions
- Acronyms BRACE
- 27 Apr 2023 Results (n=3988) published in the New England Journal of Medicine
- 12 Jul 2022 Status changed from active, no longer recruiting to completed.
- 26 Apr 2022 Planned End Date changed from 30 Mar 2022 to 12 May 2022.
Most Recent Events
Trial Overview
Purpose
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.
Primary Endpoints
COVID-19 disease incidence
description: Number of participants with COVID-19 disease defined as
positive SARS-Cov-2 test (PCR, antigen 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)
time_frame: Measured over the 6 months following randomisation
Severe COVID-19 disease incidence
description: Number of participants with severe COVID-19 disease, defined as: COVID-19 disease with hospitalisation, death, or non-hospitalised severe disease.
Non-hospitalised severe disease is defined as non-ambulant (*) for ≥ 3 consecutive days OR 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"
time_frame: Measured over the 6 months following randomisation
Other Endpoints
Symptomatic COVID-19 by 12 months
description: 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)
time_frame: Measured over the 12 months following randomisation
Severe COVID-19 incidence over 12 months
description: 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"
time_frame: Measured over the 12 months following randomisation
Time to first symptom of COVID-19
description: 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]
time_frame: Measured over the 6 and 12 months following randomisation
Number of Episodes of COVID-19
description: The total number of symptomatic or severe COVID-19 episodes (refer to outcome 3 and 4 for definitions)
time_frame: Measured over the 6 and 12 months following randomisation
Asymptomatic SARS-CoV-2 infection
description: 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
time_frame: Measured over the 6 and 12 months following randomisation
Work absenteeism due to COVID-19
description: 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)
time_frame: Measured within 6 and 12 months following randomisation
Bed confinement due to COVID-19
description: 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)
time_frame: Measured over 6 and 12 months following randomisation
Symptom duration of COVID-19
description: 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)
time_frame: Measured over 6 and12 months following randomisation
Pneumonia due to COVID-19
description: Number of pneumonia cases (using self-reported questionnaire and/or medical/hospital records) due to COVID-19
time_frame: Measured over the 6 and 12 months following randomisation
Oxygen therapy due to COVID-19
description: Need for oxygen therapy (using self-reported questionnaire and/or medical/hospital records) due to COVID-19
time_frame: Measured over the 6 and12 months following randomisation
Critical care admissions due to COVID-19
description: Number of admission to critical care (using self-reported questionnaire and/or medical/hospital records) due to COVID-19
time_frame: Measured over the 6 and 12 months following randomisation
Mechanical ventilation due to COVID-19
description: Number of participants needing mechanical ventilation (using self-reported questionnaire and/or medical/hospital records)
time_frame: Measured over the 12 months following randomisation
Hospitalisation duration with COVID-19
description: Number of days of hospitalisation due to COVID-19 (using self-reported questionnaire and/or medical/hospital records).
time_frame: Measured over the 6 and 12 months following randomisation
Mortality due to COVID-19
description: Number of deaths due to COVID-19
time_frame: Measured over the 6 and 12 months following randomisation
Fever or respiratory illness
description: 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).
time_frame: Measured over the 12 months following randomisation
Severe fever or respiratory illness
description: 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
time_frame: Measured over the 12 months following randomisation
Episodes of fever or respiratory illness
description: 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).
time_frame: Measured over the 12 months following randomisation
Work absenteeism due to fever or respiratory illness
description: 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)
time_frame: Measured over the 12 months following randomisation
Bed confinement due to fever or respiratory illness
description: 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)
time_frame: Measured over the 12 months following randomisation
Symptom duration of fever or respiratory illness
description: 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)
time_frame: Measured over the 12 months following randomisation
Pneumonia within a febrile or respiratory illness
description: Number of pneumonia cases(using self-reported questionnaire and/or medical/hospital records)
time_frame: Measured over the 12 months following randomisation
Oxygen therapy for a febrile or respiratory illness
description: Need for oxygen therapy (using self-reported questionnaire and/or medical/hospital records)
time_frame: Measured over the 12 months following randomisation
Critical care admissions for a febrile or respiratory illness
description: Number of admission to critical care (using self-reported questionnaire and/or medical/hospital records)
time_frame: Measured over the 12 months following randomisation
Mechanical ventilation for a febrile or respiratory illness
description: Number of participants needing mechanical ventilation (using self-reported questionnaire and/or medical/hospital records)
time_frame: Measured over the 12 months following randomisation
Mortality as a consequence of an episode of fever or respiratory illness
description: Number of deaths
time_frame: Measured over the 12 months following randomisation
Hospitalisation duration for a febrile or respiratory illness
description: Number of days of hospitalisation due to fever or respiratory illness (using self-reported questionnaire, medical/hospital records)
time_frame: Measured within 6 and 12 months following randomisation
Unplanned work absenteeism for an acute illness or hospitalisation
description: Number of days of unplanned absenteeism for any reason (using self-reported questionnaire)
time_frame: Measured over the 6 and 12 months following randomisation
Local and systemic adverse events to BCG vaccination in healthcare workers
description: 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.
time_frame: Measured over the 3 months following randomisation
Serious Adverse Events (SAEs) to BCG vaccination in healthcare workers
description: SAEs over the 3 months following randomisation, by type, severity (graded using toxicity grading scale), relationship to intervention.
time_frame: Measured over the 3 months following randomisation [1]
Diseases Treated
| Indication | Qualifiers | Patient Segments |
|---|---|---|
| COVID 2019 infections | prevention | - |
Biomarker
| NCT Number | Biomarker Name | Biomarker Function |
|---|---|---|
| NCT04327206 | Interferon Gamma (IFNg) | Eligibility Criteria |
Subjects
- Subject Type patients
-
Number
Planned: 10078
Actual: 6828
- Sex male & female
- Age Group ≥ 18 years; adult
Patient 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
Patient 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
Trial Details
Identifiers
| Identifier | Owner |
|---|---|
| NCT04327206 | ClinicalTrials.gov: US National Institutes of Health |
| EudraCT2020-002503-19 | European Clinical Trials Database |
| U1111-1256-4104 | World Health Organisation |
| 62586 | - |
| INV017302 | - |
Trial Dates
-
Initiation Dates
Planned : 30 Mar 2020
Actual : 30 Mar 2020
-
Primary Completion Dates
Planned : 20 Nov 2021
Actual : 10 Nov 2021
-
End Dates
Planned : 12 May 2022
Actual : 27 May 2022
Substudies/Extensions
The trial includes a pre-planned meta-analysis with data from the 2834 participants recruited in first phase of this study (in Australia only) which followed the same protocol but where participants were randomised between BCG and no BCG at the time of receiving a flu vaccination, with a total sample size of 10078. UK participants will not be part of this analysis.
Other Details
- Design double-blind; multicentre; parallel; prospective; randomised
- Phase of Trial Phase III
- Location Australia; Brazil; England; Netherlands; Spain; United Kingdom
- Focus Adverse reactions
Interventions
| Drugs | Route | Formulation |
|---|---|---|
| BCG vaccinePrimary Drug | Intradermal | Injection |
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 Name: Bacille Calmette-Guerin Vaccine, Bacillus Calmette-Guerin Vaccine, Statens Serum Institute BCG vaccine, Mycobacterium bovis BCG (Bacille Calmette Guérin), Danish Strain 1331, BCG Denmark
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 Name: 0.9% Saline
Results
Publications
-
Pittet LF, Messina NL, Orsini F, Moore CL, Abruzzo V, Barry S, et al. Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers. . N-Engl-J-Med 2023;388(17):1582-1596.
PubMed | CrossRef Fulltext
Trial Centres
Investigators
| Investigator | Centre Name | Trial Centre Country |
|---|---|---|
| Prof Nigel Curtis | Murdoch Children's Research Institute, Murdoch Childrens Research Institute |
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|
Centres
| Centre Name | Location | Trial Centre Country |
|---|---|---|
| Amphia Hospital | Breda | Netherlands |
| Bill and Melinda Gates Foundation |
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| CASSEMS Hospital | Campo Grande, Mato Grosso Do Sul | Brazil |
| Centro de Estudos da Saúde do Trabalhador e Ecologia Humana | Rio de Janeiro, RJ | Brazil |
| Centro de Referência Prof Hélio Fraga | Rio de Janeiro, RJ | Brazil |
| Epworth Richmond | Melbourne, Victoria | Australia |
| Federal University of Mato Grosso do Sul | Campo Grande, Mato Grosso Do Sul | Brazil |
| Fiona Stanley Hospital | Murdoch, Western Australia | Australia |
| Fundação de Medicina Tropical Dr Heitor Vieira Dourado (FMT-HVD) | Manaus, Amazonas | Brazil |
| Hospital Regional de Mato Grosso do Sul | Campo Grande, Mato Grosso Do Sul | Brazil |
| Ide Lane Surgery | Alphington, Exeter | United-Kingdom |
| Marqués de Valdecilla University Hospital | Santander | Spain |
| Monash Health- Monash Medical Centre | Melbourne, Victoria | Australia |
| Murdoch Children's Research Institute |
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|
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|
| Murdoch Childrens Research Institute |
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|
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|
| Mutua Terrassa Univeristy Hospital | Terrassa, Barcelona | Spain |
| Noord West Ziekenhuis | Alkmaar | Netherlands |
| Perth Children's Hospital | Perth, Western Australia | Australia |
| Prince of Wales Hospital | Sydney, New South Wales | Australia |
| Radboud UMC | Nijmegen | Netherlands |
| Rijnstate Hospital | Arnhem | Netherlands |
| Royal Adelaide Hospital | Adelaide, South Australia | Australia |
| Royal Children's Hospital |
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|
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| Royal Children's Hospital | Melbourne, Victoria | Australia |
| Royal Devon and Exeter NHS Foundation Trust | Exeter | United-Kingdom |
| Santa Casa Hospital | Campo Grande, Mato Grosso Do Sul | Brazil |
| Sir Charles Gairdner Hospital | Perth, Western Australia | Australia |
| St Antonius Hospital | Nieuwegein | Netherlands |
| St Leonard's Practice | St Leonards, Exeter | United-Kingdom |
| St Vincent's Hospital, Sydney | Sydney, New South Wales | Australia |
| Sydney Children's Hospital, Randwick | Sydney, New South Wales | Australia |
| Teign Estuary Medical Group | Teignmouth, Devon | United-Kingdom |
| The Children's Hospital at Westmead | Sydney, New South Wales | Australia |
| Travel Clinic | Exeter | United-Kingdom |
| University Hospital Cruces | Barakaldo, Bizkaia | Spain |
| University Hospital German Trias I Pujol | Badalona, Barcelona | Spain |
| University hospital in Utrecht (UMCU) | Utrecht | Netherlands |
| University Hospital Virgen Macarena | Sevilla | Spain |
| Westmead Hospital | Sydney, New South Wales | Australia |
| Women's and Children's Hospital | North Adelaide, South Australia | Australia |
Trial History
| Event Date | Event Type | Comment |
|---|---|---|
| 11 Sep 2023 | Other trial event | Last checked against European Clinical Trials Database record. Updated 11 Sep 2023 |
| 27 Apr 2023 | Results | Results (n=3988) published in the New England Journal of Medicine Updated 28 Apr 2023 |
| 18 Jul 2022 | Other trial event | Last checked against ClinicalTrials.gov record. Updated 18 Jul 2022 |
| 12 Jul 2022 | Status change - completed | Status changed from active, no longer recruiting to completed. Updated 18 Jul 2022 |
| 26 Apr 2022 | Completion date | Planned End Date changed from 30 Mar 2022 to 12 May 2022. Updated 03 May 2022 |
| 06 Feb 2022 | Other trial event | This trial has been completed in Netherland, according to European Clinical Trials Database record. Updated 08 Feb 2022 |
| 10 Nov 2021 | Other trial event | Planned primary completion date changed from 30 Jun 2021 to 20 Nov 2021. Updated 23 Nov 2021 |
| 28 Jun 2021 | Biomarker Update | Biomarkers information updated Updated 04 Nov 2021 |
| 07 Apr 2021 | Status change - active, no longer recruiting | Status changed from recruiting to active, no longer recruiting. Updated 13 Apr 2021 |
| 14 Sep 2020 | Other trial event | New source identified and integrated(European Clinical Trials Database;EudraCT2020-002503-19). Updated 14 Sep 2020 |
| 18 Aug 2020 | Other trial event | Planned primary completion date changed from 30 Oct 2020 to 30 Jun 2021. Updated 24 Aug 2020 |
| 17 May 2020 | Protocol amendment | Outcome measures, arm, study design and eligibility criteria amended. Updated 20 May 2020 |
| 17 May 2020 | Other trial event | Planned number of patients changed from 4170 to 10078. Updated 20 May 2020 |
| 02 Apr 2020 | New trial record | New trial record Updated 02 Apr 2020 |
| 01 Apr 2020 | Status change - recruiting | Status changed from not yet recruiting to recruiting. Updated 06 Apr 2020 |
Table of Contents
References
-
ClinicalTrials.gov: US National Institutes of Health. Trial-Reg 2023;.
Available from: URL: http://clinicaltrials.gov -
European Clinical Trials Database. Trial-Reg 2023;.
Available from: URL: https://www.clinicaltrialsregister.eu -
Pittet LF, Messina NL, Orsini F, Moore CL, Abruzzo V, Barry S, et al. Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers. . N-Engl-J-Med 2023;388(17):1582-1596.
PubMed | CrossRef Fulltext
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