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

Trial Profile

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

Status: Active, no longer recruiting
Phase of Trial: Phase III

Latest Information Update: 13 Apr 2021

At a glance

  • Drugs BCG vaccine (Primary)
  • Indications COVID 2019 infections
  • Focus Adverse reactions
  • Acronyms BRACE
  • Most Recent Events

    • 07 Apr 2021 Status changed from recruiting to active, no longer recruiting.
    • 18 Aug 2020 Planned primary completion date changed from 30 Oct 2020 to 30 Jun 2021.
    • 17 May 2020 Outcome measures, arm, study design and eligibility criteria amended.

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

COVID-19 incidence by 12 months

description: Number of participants with COVID-19 disease defined as
positive SARS-Cov-2 test (PCR 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 by 12 months

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 12 months following randomisation

Time to first symptom of COVID-19

description: Time to first symptom of COVID-19 in a participant who subsequently meets the case definition:
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 12 months following randomisation

Episodes of COVID-19

description: Number of episodes of 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 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 PCR or seroconversion)
Absence of respiratory illness (using self-reported questionnaire)
No evidence of exposure prior to randomisation (inclusion serology negative)
time_frame: Measured over the 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 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 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 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

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, 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 12 months following randomisation

SARS-CoV-2 pneumonia

description: Number of pneumonia cases (abnormal chest X-ray) (using self-reported questionnaire and/or medical/hospital records) associated with a positive SARS-CoV-2 test
time_frame: Measured over the 12 months following randomisation

Oxygen therapy with SARS-CoV-2

description: Need for oxygen therapy (using self-reported questionnaire and/or medical/hospital records) associated with a positive SARS-CoV-2 test
time_frame: Measured over the 12 months following randomisation

Critical care admissions with SARS-CoV-2

description: Number of admission to critical care (using self-reported questionnaire and/or medical/hospital records) associated with a positive SARS-CoV-2 test
time_frame: Measured over the 12 months following randomisation

Critical care admission duration with SARS-CoV-2

description: Number of days admitted to critical care (using self-reported questionnaire and/or medical/hospital records) associated with a positive SARS-CoV-2 test
time_frame: Measured over the 12 months following randomisation

Mechanical ventilation with SARS-CoV-2

description: Number of participants needing mechanical ventilation (using self-reported questionnaire and/or medical/hospital records) and a positive SARS-CoV-2 test
time_frame: Measured over the 12 months following randomisation

Mechanical ventilation duration with SARS-CoV-2

description: Number of days that participants needed mechanical ventilation (using self-reported questionnaire and/or medical/hospital records) and a positive SARS-CoV-2 test
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 12 months following randomisation

Mortality with SARS-CoV-2

description: Number of deaths (from death registry) associated with a positive SARS-CoV-2 test
time_frame: Measured over the 12 months following randomisation

Fever or respiratory illness

description: Number of participants with fever or respiratory illness will be 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

Episodes of fever or respiratory illness

description: Number of episodes of 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

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

description: Number of pneumonia cases (abnormal chest X-ray) (using self-reported questionnaire and/or medical/hospital records)
time_frame: Measured over the 12 months following randomisation

Oxygen therapy

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

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

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

description: Number of deaths (from death registry)
time_frame: Measured over the 12 months following randomisation

Hospitalisation duration with fever or respiratory illness

description: Number of days of hospitalisation due to fever or respiratory illness (using self-reported questionnaire, medical/hospital records and/or government registries)
time_frame: Measured over the 12 months following randomisation

Unplanned work absenteeism

description: Number of days of unplanned absenteeism for any reason (using self-reported questionnaire)
time_frame: Measured over the 12 months following randomisation

Local and systemic adverse events to BCG vaccination in healthcare workers

description: Type and severity of local and systemic adverse events will be collected in self-reported questionnaire and graded using toxicity grading scale.
time_frame: Measured over the 3 months following randomisation [1]

Diseases Treated

Indication Qualifiers Patient Segments
COVID 2019 infections prevention -

Subjects

  • Subject Type patients
  • Number

    Planned: 10078

  • 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 -

Trial Dates

  • Initiation Dates

    Planned : 30 Mar 2020

    Actual : 30 Mar 2020

  • Primary Completion Dates

    Planned : 30 Jun 2021

  • End Dates

    Planned : 30 Mar 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 multicentre; parallel; prospective; randomised; single-blind
  • 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

Trial Centres

Investigators

Investigator Centre Name Trial Centre Country
Dr Tomás Perez Porcuna, MD PhD
+34 644460736 tomasperez@mutuaterrassa.es
show details
Mutua Terrassa Univeristy Hospital Spain
Júlio Croda, MD PhD
55 67 981229959 julio.croda@fiocruz.br
show details
CASSEMS Hospital, Federal University of Mato Grosso do Sul, Hospital Regional de Mato Grosso do Sul, Santa Casa Hospital Brazil
Marcus Lacerda, MD PhD
55 92 991147633 marcuslacerda.br@gmail.com
show details
Fundação de Medicina Tropical Dr Heitor Vieira Dourado (FMT-HVD) Brazil
Margareth Dalcolmo, MD PhD
55 21 999894904 margarethdalcolmo@ensp.fiocruz.br
show details
Centro de Estudos da Saúde do Trabalhador e Ecologia Humana, Centro de Referência Prof Hélio Fraga Brazil
Prof Nigel Curtis Murdoch Children's Research Institute
-
Prof Nigel Curtis, MBBS PhD
+613 93456366 nigel.curtis@rch.org.au
show details
-

Centres

Centre Name Location Trial Centre Country
-
-
-
Amphia Hospital Breda Netherlands
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
-
-
Murdoch Childrens Research Institute
-
-
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
-
-
Royal Children's Hospital Melbourne, Victoria Australia
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
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
13 Apr 2021 Other trial event Last checked against ClinicalTrials.gov record. Updated 13 Apr 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

References

  1. ClinicalTrials.gov: US National Institutes of Health. Trial-Reg 2016;.

    Available from: URL: http://clinicaltrials.gov
  2. European Clinical Trials Database. Trial-Reg 2016;.

    Available from: URL: https://www.clinicaltrialsregister.eu
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