BCG Vaccination to Protect Healthcare Workers Against COVID-19

Study Overview
=================
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.

Official Title
-----------------
BCG Vaccination to Reduce the Impact of COVID-19 in Healthcare Workers (BRACE) Trial

Conditions
-----------------
Respiratory Illness, Coronavirus Disease 2019 (COVID-19), Corona Virus Infection, COVID-19

Intervention / Treatment
-----------------
* Drug: BCG Vaccine
* Drug: 0.9%NaCl


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase III, two group, multicentre, randomised controlled trial
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BCG vaccine<br>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<br>* 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<br>* Other names: BCG Denmark;|
| Placebo Comparator: 0.9% Saline<br>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<br>* 0.9% Sodium Chloride Injection<br>* Other names: 0.9% Saline;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptomatic COVID-19 by 6 months | 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) | Measured over the 6 months following randomisation | 
| Severe COVID-19 incidence over 6 months | 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 | Measured over the 6 months following randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptomatic COVID-19 by 12 months | 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) | Measured over the 12 months following randomisation | 
| Severe COVID-19 incidence over 12 months | 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 | Measured over the 12 months following randomisation | 
| Time to first symptom of COVID-19 | 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] | Measured over the 6 and 12 months following randomisation | 
| Number of Episodes of COVID-19 | The total number of symptomatic or severe COVID-19 episodes (refer to outcome 3 and 4 for definitions) | Measured over the 6 and 12 months following randomisation | 
| Asymptomatic SARS-CoV-2 infection | 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 | Measured over the 6 and 12 months following randomisation | 
| Work absenteeism due to COVID-19 | 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) | Measured within 6 and 12 months following randomisation | 
| Bed confinement due to COVID-19 | 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) | Measured over 6 and 12 months following randomisation | 
| Symptom duration of COVID-19 | 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) | Measured over 6 and12 months following randomisation | 
| Pneumonia due to COVID-19 | Number of pneumonia cases (using self-reported questionnaire and/or medical/hospital records) due to COVID-19 | Measured over the 6 and 12 months following randomisation | 
| Oxygen therapy due to COVID-19 | Need for oxygen therapy (using self-reported questionnaire and/or medical/hospital records) due to COVID-19 | Measured over the 6 and12 months following randomisation | 
| Critical care admissions due to COVID-19 | Number of admission to critical care (using self-reported questionnaire and/or medical/hospital records) due to COVID-19 | Measured over the 6 and 12 months following randomisation | 
| Mechanical ventilation due to COVID-19 | Number of participants needing mechanical ventilation (using self-reported questionnaire and/or medical/hospital records) | Measured over the 12 months following randomisation | 
| Hospitalisation duration with COVID-19 | Number of days of hospitalisation due to COVID-19 (using self-reported questionnaire and/or medical/hospital records). | Measured over the 6 and 12 months following randomisation | 
| Mortality due to COVID-19 | Number of deaths due to COVID-19 | Measured over the 6 and 12 months following randomisation | 
| Fever or respiratory illness | 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). | Measured over the 12 months following randomisation | 
| Severe fever or respiratory illness | 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 | Measured over the 12 months following randomisation | 
| Episodes of fever or respiratory illness | 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). | Measured over the 12 months following randomisation | 
| Work absenteeism due to fever or respiratory illness | 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) | Measured over the 12 months following randomisation | 
| Bed confinement due to fever or respiratory illness | 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) | Measured over the 12 months following randomisation | 
| Symptom duration of fever or respiratory illness | 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) | Measured over the 12 months following randomisation | 
| Pneumonia within a febrile or respiratory illness | Number of pneumonia cases(using self-reported questionnaire and/or medical/hospital records) | Measured over the 12 months following randomisation | 
| Oxygen therapy for a febrile or respiratory illness | Need for oxygen therapy (using self-reported questionnaire and/or medical/hospital records) | Measured over the 12 months following randomisation | 
| Critical care admissions for a febrile or respiratory illness | Number of admission to critical care (using self-reported questionnaire and/or medical/hospital records) | Measured over the 12 months following randomisation | 
| Mechanical ventilation for a febrile or respiratory illness | Number of participants needing mechanical ventilation (using self-reported questionnaire and/or medical/hospital records) | Measured over the 12 months following randomisation | 
| Mortality as a consequence of an episode of fever or respiratory illness | Number of deaths | Measured over the 12 months following randomisation | 
| Hospitalisation duration for a febrile or respiratory illness | Number of days of hospitalisation due to fever or respiratory illness (using self-reported questionnaire, medical/hospital records) | Measured within 6 and 12 months following randomisation | 
| Unplanned work absenteeism for an acute illness or hospitalisation | Number of days of unplanned absenteeism for any reason (using self-reported questionnaire) | Measured over the 6 and 12 months following randomisation | 
| Local and systemic adverse events to BCG vaccination in healthcare workers | 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. | Measured over the 3 months following randomisation | 
| Serious Adverse Events (SAEs) to BCG vaccination in healthcare workers | SAEs over the 3 months following randomisation, by type, severity (graded using toxicity grading scale), relationship to intervention. | Measured over the 3 months following randomisation |