BCG Vaccination to Protect Healthcare Workers Against COVID-19
- Conditions
- Coronavirus Disease 2019 (COVID-19)COVID-19Respiratory IllnessCorona Virus Infection
- Interventions
- Drug: 0.9%NaCl
- Registration Number
- NCT04327206
- Lead Sponsor
- Murdoch Childrens Research Institute
- 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.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 6828
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Over 18 years of age
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Healthcare worker
- This is defined as anyone who works in a healthcare setting or has face to face contact with patients.
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Provide a signed and dated informed consent form
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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.
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Pre-randomisation blood collected
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Has any BCG vaccine contraindication
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Fever or generalised skin infection (where feasible, randomisation can be delayed until cleared)
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Weakened resistance toward infections due to a disease in/of the immune system
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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).
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People with congenital cellular immunodeficiencies, including specific deficiencies of the interferon-gamma pathway
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People with malignancies involving bone marrow or lymphoid systems
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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
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Known or suspected HIV infection,even if they are asymptomatic or have normal immune function.
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This is because of the risk of disseminated BCG infection
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People with active skin disease such as eczema, dermatitis or psoriasis at or near the site of vaccination
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A different adjacent site on the upper arm can be chosen if necessary
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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.
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Another live vaccine administered in the month prior to randomisation
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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
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Known anaphylactic reaction to any of the ingredients present in the BCG vaccine
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Previous active TB disease
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Currently receiving long term (more than 1 month) treatment with isoniazid, rifampicin or quinolone as these antibiotics have activity against Mycobacterium bovis
-
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Previous adverse reaction to BCG vaccine (significant local reaction (abscess) or suppurative lymphadenitis)
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BCG vaccine given within the last year
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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)
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Already part of this trial, recruited at a different site/hospital.
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Participation in another COVID-19 prevention trial
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Have previously received a COVID-19-specific vaccine
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description 0.9% Saline 0.9%NaCl 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). BCG vaccine 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).
- Primary Outcome Measures
Name Time Method Symptomatic COVID-19 by 6 months Measured over the 6 months following randomisation 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)Severe COVID-19 incidence over 6 months Measured over the 6 months following randomisation 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"
- Secondary Outcome Measures
Name Time Method Critical care admissions due to COVID-19 Measured over the 6 and 12 months following randomisation Number of admission to critical care (using self-reported questionnaire and/or medical/hospital records) due to COVID-19
Hospitalisation duration with COVID-19 Measured over the 6 and 12 months following randomisation Number of days of hospitalisation due to COVID-19 (using self-reported questionnaire and/or medical/hospital records).
Number of Episodes of COVID-19 Measured over the 6 and 12 months following randomisation The total number of symptomatic or severe COVID-19 episodes (refer to outcome 3 and 4 for definitions)
Work absenteeism due to COVID-19 Measured within 6 and 12 months following randomisation 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)Symptom duration of COVID-19 Measured over 6 and12 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, 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 to first symptom of COVID-19 Measured over the 6 and 12 months following randomisation 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:
\[Earliest censoring date - date of randomisation\]Asymptomatic SARS-CoV-2 infection Measured over the 6 and 12 months following randomisation 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 randomisationOxygen therapy for a febrile or respiratory illness Measured over the 12 months following randomisation Need for oxygen therapy (using self-reported questionnaire and/or medical/hospital records)
Symptomatic COVID-19 by 12 months Measured over the 12 months following randomisation 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)Severe COVID-19 incidence over 12 months Measured over the 12 months following randomisation 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"Bed confinement due to COVID-19 Measured over 6 and 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, 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)Mortality due to COVID-19 Measured over the 6 and 12 months following randomisation Number of deaths due to COVID-19
Unplanned work absenteeism for an acute illness or hospitalisation Measured over the 6 and 12 months following randomisation Number of days of unplanned absenteeism for any reason (using self-reported questionnaire)
Pneumonia due to COVID-19 Measured over the 6 and 12 months following randomisation Number of pneumonia cases (using self-reported questionnaire and/or medical/hospital records) due to COVID-19
Oxygen therapy due to COVID-19 Measured over the 6 and12 months following randomisation Need for oxygen therapy (using self-reported questionnaire and/or medical/hospital records) due to COVID-19
Mechanical ventilation due to COVID-19 Measured over the 12 months following randomisation Number of participants needing mechanical ventilation (using self-reported questionnaire and/or medical/hospital records)
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)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)Pneumonia within a febrile or respiratory illness Measured over the 12 months following randomisation Number of pneumonia cases(using self-reported questionnaire and/or medical/hospital records)
Mechanical ventilation for a febrile or respiratory illness Measured over the 12 months following randomisation Number of participants needing mechanical ventilation (using self-reported questionnaire and/or medical/hospital records)
Serious Adverse Events (SAEs) to BCG vaccination in healthcare workers Measured over the 3 months following randomisation SAEs over the 3 months following randomisation, by type, severity (graded using toxicity grading scale), relationship to intervention.
Fever or respiratory illness Measured over the 12 months following randomisation 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).Critical care admissions for a febrile or respiratory illness Measured over the 12 months following randomisation Number of admission to critical care (using self-reported questionnaire and/or medical/hospital records)
Hospitalisation duration for a febrile or respiratory illness Measured within 6 and 12 months following randomisation Number of days of hospitalisation due to fever or respiratory illness (using self-reported questionnaire, medical/hospital records)
Severe fever or respiratory illness Measured over the 12 months following randomisation 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 daysEpisodes of fever or respiratory illness Measured over the 12 months following randomisation 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).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)Mortality as a consequence of an episode of fever or respiratory illness Measured over the 12 months following randomisation Number of deaths
Local and systemic adverse events to BCG vaccination in healthcare workers Measured over the 3 months following randomisation 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.
Trial Locations
- Locations (36)
Prince of Wales Hospital
🇦🇺Sydney, New South Wales, Australia
Westmead Hospital
🇦🇺Sydney, New South Wales, Australia
Fundação de Medicina Tropical Dr Heitor Vieira Dourado (FMT-HVD)
🇧🇷Manaus, Amazonas, 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
Marqués de Valdecilla University Hospital
🇪🇸Santander, Spain
St Leonard's Practice
🇬🇧St Leonards, Exeter, United Kingdom
Royal Devon and Exeter NHS Foundation Trust
🇬🇧Exeter, United Kingdom
Perth Children's Hospital
🇦🇺Perth, Western Australia, Australia
University Hospital Cruces
🇪🇸Barakaldo, Bizkaia, Spain
Sir Charles Gairdner Hospital
🇦🇺Perth, Western Australia, Australia
Hospital Regional de Mato Grosso do Sul
🇧🇷Campo Grande, Mato Grosso Do Sul, Brazil
Fiona Stanley Hospital
🇦🇺Murdoch, Western Australia, Australia
Noord West Ziekenhuis
🇳🇱Alkmaar, Netherlands
St Antonius Hospital
🇳🇱Nieuwegein, Netherlands
Radboud UMC
🇳🇱Nijmegen, Netherlands
University hospital in Utrecht (UMCU)
🇳🇱Utrecht, Netherlands
St Vincent's Hospital, Sydney
🇦🇺Sydney, New South Wales, Australia
Sydney Children's Hospital, Randwick
🇦🇺Sydney, New South Wales, Australia
Royal Adelaide Hospital
🇦🇺Adelaide, South Australia, Australia
The Children's Hospital at Westmead
🇦🇺Sydney, New South Wales, Australia
Royal Children's Hospital
🇦🇺Melbourne, Victoria, Australia
Women's and Children's Hospital
🇦🇺North Adelaide, South Australia, Australia
Epworth Richmond
🇦🇺Melbourne, Victoria, Australia
Santa Casa Hospital
🇧🇷Campo Grande, Mato Grosso Do Sul, Brazil
CASSEMS Hospital
🇧🇷Campo Grande, Mato Grosso Do Sul, Brazil
Federal University of Mato Grosso do Sul
🇧🇷Campo Grande, Mato Grosso Do Sul, Brazil
Rijnstate Hospital
🇳🇱Arnhem, Netherlands
University Hospital German Trias I Pujol
🇪🇸Badalona, Barcelona, Spain
University Hospital Virgen Macarena
🇪🇸Sevilla, Spain
Mutua Terrassa Univeristy Hospital
🇪🇸Terrassa, Barcelona, Spain
Teign Estuary Medical Group
🇬🇧Teignmouth, Devon, United Kingdom
Ide Lane Surgery
🇬🇧Alphington, Exeter, United Kingdom
Travel Clinic
🇬🇧Exeter, United Kingdom
Amphia Hospital
🇳🇱Breda, Netherlands
Monash Health- Monash Medical Centre
🇦🇺Melbourne, Victoria, Australia