Clinical trial NCT04327206: BCG Vaccination to Protect Healthcare Workers Against COVID-19
Official title: BCG Vaccination to Reduce the Impact of COVID-19 in Healthcare Workers (BRACE) Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Coronavirus Disease 2019 (COVID-19)
Respiratory Illness
Corona Virus Infection
COVID-19
Lead sponsor: Murdoch Childrens Research Institute
Sponsor class: OTHER
Collaborators: name: Royal Children's Hospital
name: Bill and Melinda Gates Foundation
First posted: 2020-03-31
Enrollment: 6828
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase III, two group, multicentre, randomised controlled trial
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Symptomatic COVID-19 by 6 months
timeFrame: Measured over the 6 months following randomisation
measure: Severe COVID-19 incidence over 6 months
timeFrame: Measured over the 6 months following randomisation
Secondary outcomes:
measure: Symptomatic COVID-19 by 12 months
timeFrame: Measured over the 12 months following randomisation
measure: Severe COVID-19 incidence over 12 months
timeFrame: Measured over the 12 months following randomisation
measure: Time to first symptom of COVID-19
timeFrame: Measured over the 6 and 12 months following randomisation
measure: Number of Episodes of COVID-19
timeFrame: Measured over the 6 and 12 months following randomisation
measure: Asymptomatic SARS-CoV-2 infection
timeFrame: Measured over the 6 and 12 months following randomisation
measure: Work absenteeism due to COVID-19
timeFrame: Measured within 6 and 12 months following randomisation
measure: Bed confinement due to COVID-19
timeFrame: Measured over 6 and 12 months following randomisation
measure: Symptom duration of COVID-19
timeFrame: Measured over 6 and12 months following randomisation
measure: Pneumonia due to COVID-19
timeFrame: Measured over the 6 and 12 months following randomisation
measure: Oxygen therapy due to COVID-19
timeFrame: Measured over the 6 and12 months following randomisation
measure: Critical care admissions due to COVID-19
timeFrame: Measured over the 6 and 12 months following randomisation
measure: Mechanical ventilation due to COVID-19
timeFrame: Measured over the 12 months following randomisation
measure: Hospitalisation duration with COVID-19
timeFrame: Measured over the 6 and 12 months following randomisation
measure: Mortality due to COVID-19
timeFrame: Measured over the 6 and 12 months following randomisation
measure: Fever or respiratory illness
timeFrame: Measured over the 12 months following randomisation
measure: Severe fever or respiratory illness
timeFrame: Measured over the 12 months following randomisation
measure: Episodes of fever or respiratory illness
timeFrame: Measured over the 12 months following randomisation
measure: Work absenteeism due to fever or respiratory illness
timeFrame: Measured over the 12 months following randomisation
measure: Bed confinement due to fever or respiratory illness
timeFrame: Measured over the 12 months following randomisation
measure: Symptom duration of fever or respiratory illness
timeFrame: Measured over the 12 months following randomisation
measure: Pneumonia within a febrile or respiratory illness
timeFrame: Measured over the 12 months following randomisation
measure: Oxygen therapy for a febrile or respiratory illness
timeFrame: Measured over the 12 months following randomisation
measure: Critical care admissions for a febrile or respiratory illness
timeFrame: Measured over the 12 months following randomisation
measure: Mechanical ventilation for a febrile or respiratory illness
timeFrame: Measured over the 12 months following randomisation
measure: Mortality as a consequence of an episode of fever or respiratory illness
timeFrame: Measured over the 12 months following randomisation
measure: Hospitalisation duration for a febrile or respiratory illness
timeFrame: Measured within 6 and 12 months following randomisation
measure: Unplanned work absenteeism for an acute illness or hospitalisation
timeFrame: Measured over the 6 and 12 months following randomisation
measure: Local and systemic adverse events to BCG vaccination in healthcare workers
timeFrame: Measured over the 3 months following randomisation
measure: Serious Adverse Events (SAEs) to BCG vaccination in healthcare workers
timeFrame: Measured over the 3 months following randomisation
Other outcomes:
Locations:
city: Sydney
country: Australia
facility: St Vincent's Hospital, Sydney
state: New South Wales
city: Sydney
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Sydney Children's Hospital, Randwick
state: New South Wales
city: Sydney
country: Australia
facility: The Children's Hospital at Westmead
state: New South Wales
city: Sydney
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: North Adelaide
country: Australia
facility: Women's and Children's Hospital
state: South Australia
city: Melbourne
country: Australia
facility: Royal Children's Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Epworth Richmond
state: Victoria
city: Melbourne
country: Australia
facility: Monash Health- Monash Medical Centre
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Perth
country: Australia
facility: Perth Children's Hospital
state: Western Australia
city: Perth
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Manaus
country: Brazil
facility: Fundação de Medicina Tropical Dr Heitor Vieira Dourado (FMT-HVD)
state: Amazonas
city: Campo Grande
country: Brazil
facility: Santa Casa Hospital
state: Mato Grosso Do Sul
city: Campo Grande
country: Brazil
facility: CASSEMS Hospital
state: Mato Grosso Do Sul
city: Campo Grande
country: Brazil
facility: Federal University of Mato Grosso do Sul
state: Mato Grosso Do Sul
city: Campo Grande
country: Brazil
facility: Hospital Regional de Mato Grosso do Sul
state: Mato Grosso Do Sul
city: Rio de Janeiro
country: Brazil
facility: Centro de Estudos da Saúde do Trabalhador e Ecologia Humana
state: RJ
city: Rio de Janeiro
country: Brazil
facility: Centro de Referência Prof Hélio Fraga
state: RJ
city: Alkmaar
country: Netherlands
facility: Noord West Ziekenhuis
city: Arnhem
country: Netherlands
facility: Rijnstate Hospital
city: Breda
country: Netherlands
facility: Amphia Hospital
city: Nieuwegein
country: Netherlands
facility: St Antonius Hospital
city: Nijmegen
country: Netherlands
facility: Radboud UMC
city: Utrecht
country: Netherlands
facility: University hospital in Utrecht (UMCU)
city: Badalona
country: Spain
facility: University Hospital German Trias I Pujol
state: Barcelona
city: Terrassa
country: Spain
facility: Mutua Terrassa Univeristy Hospital
state: Barcelona
city: Barakaldo
country: Spain
facility: University Hospital Cruces
state: Bizkaia
city: Santander
country: Spain
facility: Marqués de Valdecilla University Hospital
city: Sevilla
country: Spain
facility: University Hospital Virgen Macarena
city: Teignmouth
country: United Kingdom
facility: Teign Estuary Medical Group
state: Devon
city: Alphington
country: United Kingdom
facility: Ide Lane Surgery
state: Exeter
city: St Leonards
country: United Kingdom
facility: St Leonard's Practice
state: Exeter
city: Exeter
country: United Kingdom
facility: Travel Clinic
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter NHS Foundation Trust
Study officials:
affiliation: Murdoch Childrens Research Institute
name: Prof Nigel Curtis
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pittet LF, Messina NL, Gardiner K, Orsini F, Abruzzo V, Bannister S, Bonten M, Campbell JL, Croda J, Dalcolmo M, Elia S, Germano S, Goodall C, Gwee A, Jamieson T, Jardim B, Kollmann TR, Guimaraes Lacerda MV, Lee KJ, Legge D, Lucas M, Lynn DJ, McDonald E, Manning L, Munns CF, Perrett KP, Prat Aymerich C, Richmond P, Shann F, Sudbury E, Villanueva P, Wood NJ, Lieschke K, Subbarao K, Davidson A, Curtis N; BRACE trial Consortium Group. BCG vaccination to reduce the impact of COVID-19 in healthcare workers: Protocol for a randomised controlled trial (BRACE trial). BMJ Open. 2021 Oct 28;11(10):e052101. doi: 10.1136/bmjopen-2021-052101.
citation: Crisan-Dabija R, Grigorescu C, Pavel CA, Artene B, Popa IV, Cernomaz A, Burlacu A. Tuberculosis and COVID-19: Lessons from the Past Viral Outbreaks and Possible Future Outcomes. Can Respir J. 2020 Sep 5;2020:1401053. doi: 10.1155/2020/1401053. eCollection 2020.