BRACE: BCG Vaccination to Protect Healthcare Workers Against COVID-19

Sponsor
Murdoch Childrens Research Institute (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT04327206
Collaborator
Royal Children's Hospital (Other), Bill and Melinda Gates Foundation (Other)
10,078
Enrollment
36
Locations
2
Arms
24
Anticipated Duration (Months)
279.9
Patients Per Site
11.7
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or DiseaseIntervention/TreatmentPhase
Phase 3

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 first phase of this study, where participants were randomised to receive BCG or no BCG vaccine at the time of receiving influenza vaccination.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
10078 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
Phase III, two group, multicentre, randomised controlled trialPhase III, two group, multicentre, randomised controlled trial
Masking:
Double (Participant, Outcomes Assessor)
Masking Description:
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.
Primary Purpose:
Prevention
Official Title:
BCG Vaccination to Reduce the Impact of COVID-19 in Healthcare Workers (BRACE) Trial
Actual Study Start Date :
Mar 30, 2020
Anticipated Primary Completion Date :
Nov 20, 2021
Anticipated Study Completion Date :
Mar 30, 2022

Arms and Interventions

ArmIntervention/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
  • Outcome Measures

    Primary Outcome Measures

    1. COVID-19 disease incidence [Measured over the 6 months following randomisation]

      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)

    2. Severe COVID-19 disease incidence [Measured over the 6 months following randomisation]

      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"

    Secondary Outcome Measures

    1. COVID-19 incidence by 12 months [Measured over the 12 months following randomisation]

      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)

    2. Severe COVID-19 incidence by 12 months [Measured over the 12 months following randomisation]

      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"

    3. Time to first symptom of COVID-19 [Measured over the 12 months following randomisation]

      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)

    4. Episodes of COVID-19 [Measured over the 12 months following randomisation]

      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)

    5. Asymptomatic SARS-CoV-2 infection [Measured over the 12 months following randomisation]

      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)

    6. Work absenteeism due to COVID-19 [Measured over the 12 months following randomisation]

      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)

    7. Bed confinement due to COVID-19 [Measured over the 12 months following randomisation]

      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)

    8. Symptom duration of COVID-19 [Measured over the 12 months following randomisation]

      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)

    9. SARS-CoV-2 pneumonia [Measured over the 12 months following randomisation]

      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

    10. Oxygen therapy with SARS-CoV-2 [Measured over the 12 months following randomisation]

      Need for oxygen therapy (using self-reported questionnaire and/or medical/hospital records) associated with a positive SARS-CoV-2 test

    11. Critical care admissions with SARS-CoV-2 [Measured over the 12 months following randomisation]

      Number of admission to critical care (using self-reported questionnaire and/or medical/hospital records) associated with a positive SARS-CoV-2 test

    12. Critical care admission duration with SARS-CoV-2 [Measured over the 12 months following randomisation]

      Number of days admitted to critical care (using self-reported questionnaire and/or medical/hospital records) associated with a positive SARS-CoV-2 test

    13. Mechanical ventilation with SARS-CoV-2 [Measured over the 12 months following randomisation]

      Number of participants needing mechanical ventilation (using self-reported questionnaire and/or medical/hospital records) and a positive SARS-CoV-2 test

    14. Mechanical ventilation duration with SARS-CoV-2 [Measured over the 12 months following randomisation]

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

    15. Hospitalisation duration with COVID-19 [Measured over the 12 months following randomisation]

      Number of days of hospitalisation due to COVID-19 (using self-reported questionnaire and/or medical/hospital records).

    16. Mortality with SARS-CoV-2 [Measured over the 12 months following randomisation]

      Number of deaths (from death registry) associated with a positive SARS-CoV-2 test

    17. Fever or respiratory illness [Measured over the 12 months following randomisation]

      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)

    18. Episodes of fever or respiratory illness [Measured over the 12 months following randomisation]

      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)

    19. Work absenteeism due to fever or respiratory illness [Measured over the 12 months following randomisation]

      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)

    20. Bed confinement due to fever or respiratory illness [Measured over the 12 months following randomisation]

      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)

    21. Symptom duration of fever or respiratory illness [Measured over the 12 months following randomisation]

      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)

    22. Pneumonia [Measured over the 12 months following randomisation]

      Number of pneumonia cases (abnormal chest X-ray) (using self-reported questionnaire and/or medical/hospital records)

    23. Oxygen therapy [Measured over the 12 months following randomisation]

      Need for oxygen therapy (using self-reported questionnaire and/or medical/hospital records)

    24. Critical care admissions [Measured over the 12 months following randomisation]

      Number of admission to critical care (using self-reported questionnaire and/or medical/hospital records)

    25. Mechanical ventilation [Measured over the 12 months following randomisation]

      Number of participants needing mechanical ventilation (using self-reported questionnaire and/or medical/hospital records)

    26. Mortality [Measured over the 12 months following randomisation]

      Number of deaths (from death registry)

    27. Hospitalisation duration with fever or respiratory illness [Measured over the 12 months following randomisation]

      Number of days of hospitalisation due to fever or respiratory illness (using self-reported questionnaire, medical/hospital records and/or government registries)

    28. Unplanned work absenteeism [Measured over the 12 months following randomisation]

      Number of days of unplanned absenteeism for any reason (using self-reported questionnaire)

    29. Local and systemic adverse events to BCG vaccination in healthcare workers [Measured over the 3 months following randomisation]

      Type and severity of local and systemic adverse events will be collected in self-reported questionnaire and graded using toxicity grading scale.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    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

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1St Vincent's Hospital, SydneySydneyNew South WalesAustralia2010
    2Prince of Wales HospitalSydneyNew South WalesAustralia2031
    3Sydney Children's Hospital, RandwickSydneyNew South WalesAustralia2145
    4The Children's Hospital at WestmeadSydneyNew South WalesAustralia2145
    5Westmead HospitalSydneyNew South WalesAustralia2145
    6Royal Adelaide HospitalAdelaideSouth AustraliaAustralia5000
    7Women's and Children's HospitalNorth AdelaideSouth AustraliaAustralia5006
    8Royal Children's HospitalMelbourneVictoriaAustralia3052
    9Epworth RichmondMelbourneVictoriaAustralia3121
    10Monash Health- Monash Medical CentreMelbourneVictoriaAustralia3168
    11Fiona Stanley HospitalMurdochWestern AustraliaAustralia6150
    12Perth Children's HospitalPerthWestern AustraliaAustralia6009
    13Sir Charles Gairdner HospitalPerthWestern AustraliaAustralia6009
    14Fundação de Medicina Tropical Dr Heitor Vieira Dourado (FMT-HVD)ManausAmazonasBrazil69040-000
    15Santa Casa HospitalCampo GrandeMato Grosso Do SulBrazil79002-230
    16CASSEMS HospitalCampo GrandeMato Grosso Do SulBrazil79002-251
    17Federal University of Mato Grosso do SulCampo GrandeMato Grosso Do SulBrazil79070-900
    18Hospital Regional de Mato Grosso do SulCampo GrandeMato Grosso Do SulBrazil79084-180
    19Centro de Estudos da Saúde do Trabalhador e Ecologia HumanaRio de JaneiroRJBrazil22780-195
    20Centro de Referência Prof Hélio FragaRio de JaneiroRJBrazil22780-195
    21Noord West ZiekenhuisAlkmaarNetherlands1815 JD
    22Rijnstate HospitalArnhemNetherlands6815 AD
    23Amphia HospitalBredaNetherlands4818 CK
    24St Antonius HospitalNieuwegeinNetherlands3435 CM
    25Radboud UMCNijmegenNetherlands6525 GA
    26University hospital in Utrecht (UMCU)UtrechtNetherlands3584 CX
    27University Hospital German Trias I PujolBadalonaBarcelonaSpain08916
    28Mutua Terrassa Univeristy HospitalTerrassaBarcelonaSpain08221
    29University Hospital CrucesBarakaldoBizkaiaSpain48903
    30Marqués de Valdecilla University HospitalSantanderSpain39008
    31University Hospital Virgen MacarenaSevillaSpain41009
    32Teign Estuary Medical GroupTeignmouthDevonUnited KingdomTQ14 8AB
    33Ide Lane SurgeryAlphingtonExeterUnited KingdomEX2 8UP
    34St Leonard's PracticeSt LeonardsExeterUnited KingdomEX1 1SB
    35Travel ClinicExeterUnited KingdomEX1 1PR
    36Royal Devon and Exeter NHS Foundation TrustExeterUnited KingdomEX2 5DW

    Sponsors and Collaborators

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

    Investigators

    • Principal Investigator: Prof Nigel Curtis, Murdoch Children's Research Institute

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Murdoch Childrens Research Institute
    ClinicalTrials.gov Identifier:
    NCT04327206
    Other Study ID Numbers:
    • 62586
    • U1111-1256-4104
    • INV-017302
    First Posted:
    Mar 31, 2020
    Last Update Posted:
    Nov 18, 2021
    Last Verified:
    Nov 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Nov 18, 2021