Coronavirus Disease 2019 (COVID-19), Respiratory Illness, Corona Virus Infection, COVID-19
Conditions
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.
Interventions
DRUGBCG 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
DRUG0.9%NaCl
0.9% Sodium Chloride Injection
Sponsors
Royal Children's Hospital
Bill and Melinda Gates Foundation
Murdoch Childrens Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, 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.
Intervention model description
Phase III, two group, multicentre, randomised controlled trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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: \[Earliest censoring date - date of randomisation\] |
| 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) |
| 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 randomisation |
| 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) |
| 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) |
| 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) |
| 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 |
| 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 |
| 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) |
| 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). |
| Mortality due to COVID-19 | Measured over the 6 and 12 months following randomisation | Number of deaths due to COVID-19 |
| 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). |
| 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) |
| Episodes 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). |
| 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) |
| 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) |
| 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) |
| Oxygen 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) |
| 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) |
| 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) |
| Mortality as a consequence of an episode of fever or respiratory illness | Measured over the 12 months following randomisation | Number of deaths |
| 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) |
| 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) |
| 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. |
| 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. |
| 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 days |
| 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 |
Countries
Australia, Brazil, Netherlands, Spain, United Kingdom
Outcome results
None listed