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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT04327206
Other study ID # 62586
Secondary ID U1111-1256-4104I
Status Completed
Phase Phase 3
First received
Last updated
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
Health authority
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

Study Design


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
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