BCG Vaccination to Protect Healthcare Workers Against COVID-19

COVID-19 Clinical Trial

— BRACE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04327206
• Other study ID #: 62586
• Secondary ID: U1111-1256-4104I
• Status: Completed
• Phase: Phase 3
• Start date: March 30, 2020
• Est. completion date: May 27, 2022

Study information

• Verified date: August 2022
• Source: Murdoch Childrens Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 6828
• Est. completion date: May 27, 2022
• Est. primary completion date: November 10, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Corona Virus Infection
• Coronavirus Disease 2019 (COVID-19)
• Coronavirus Infections
• COVID-19
• Respiratory Illness

Intervention

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
• 0.9%NaCl
0.9% Sodium Chloride Injection

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Epworth Richmond	Melbourne	Victoria
Australia	Monash Health- Monash Medical Centre	Melbourne	Victoria
Australia	Royal Children's Hospital	Melbourne	Victoria
Australia	Fiona Stanley Hospital	Murdoch	Western Australia
Australia	Women's and Children's Hospital	North Adelaide	South Australia
Australia	Perth Children's Hospital	Perth	Western Australia
Australia	Sir Charles Gairdner Hospital	Perth	Western Australia
Australia	Prince of Wales Hospital	Sydney	New South Wales
Australia	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	Westmead Hospital	Sydney	New South Wales
Brazil	CASSEMS Hospital	Campo Grande	Mato Grosso Do Sul
Brazil	Federal University of Mato Grosso do Sul	Campo Grande	Mato Grosso Do Sul
Brazil	Hospital Regional de Mato Grosso do Sul	Campo Grande	Mato Grosso Do Sul
Brazil	Santa Casa Hospital	Campo Grande	Mato Grosso Do Sul
Brazil	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
Netherlands	Noord West Ziekenhuis	Alkmaar
Netherlands	Rijnstate Hospital	Arnhem
Netherlands	Amphia Hospital	Breda
Netherlands	St Antonius Hospital	Nieuwegein
Netherlands	Radboud UMC	Nijmegen
Netherlands	University hospital in Utrecht (UMCU)	Utrecht
Spain	University Hospital German Trias I Pujol	Badalona	Barcelona
Spain	University Hospital Cruces	Barakaldo	Bizkaia
Spain	Marqués de Valdecilla University Hospital	Santander
Spain	University Hospital Virgen Macarena	Sevilla
Spain	Mutua Terrassa Univeristy Hospital	Terrassa	Barcelona
United Kingdom	Ide Lane Surgery	Alphington	Exeter
United Kingdom	Royal Devon and Exeter NHS Foundation Trust	Exeter
United Kingdom	Travel Clinic	Exeter
United Kingdom	St Leonard's Practice	St Leonards	Exeter
United Kingdom	Teign Estuary Medical Group	Teignmouth	Devon

Sponsors (3)

Lead Sponsor	Collaborator
Murdoch Childrens Research Institute	Bill and Melinda Gates Foundation, Royal Children's Hospital

Countries where clinical trial is conducted

Australia,  Brazil,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Mortality due to COVID-19	Number of deaths due to COVID-19	Measured over the 6 and 12 months following randomisation
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Mortality as a consequence of an episode of fever or respiratory illness	Number of deaths	Measured over the 12 months following randomisation
Secondary	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
Secondary	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
Secondary	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
Secondary	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