BRACE: BCG Vaccination to Protect Healthcare Workers Against COVID-19

• Sponsor: Murdoch Childrens Research Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT04327206
• Collaborator: Royal Children's Hospital (Other), Bill and Melinda Gates Foundation (Other)
• Enrollment: 6,828
• Locations: 36
• Arms: 2
• Actual Duration (Months): 25.9
• Patients Per Site: 189.7
• Patients Per Site Per Month: 7.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Coronavirus Disease 2019 (COVID-19); Respiratory Illness; Corona Virus Infection; COVID-19	Drug: BCG Vaccine; Drug: 0.9%NaCl	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 6828 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Phase III, two group, multicentre, randomised controlled trialPhase III, two group, multicentre, randomised controlled trial
• Masking: Double (Participant, 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.
• Primary Purpose: Prevention
• Official Title: BCG Vaccination to Reduce the Impact of COVID-19 in Healthcare Workers (BRACE) Trial
• Actual Study Start Date: Mar 30, 2020
• Actual Primary Completion Date: Nov 10, 2021
• Actual Study Completion Date: May 27, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BCG vaccine 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; 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; Other Names: Bacille Calmette-Guerin Vaccine Bacillus Calmette-Guerin Vaccine Statens Serum Institute BCG vaccine Mycobacterium bovis BCG (Bacille Calmette Guérin), Danish Strain 1331 BCG Denmark
Placebo Comparator: 0.9% Saline 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; 0.9% Sodium Chloride Injection; Other Names: 0.9% Saline

Outcome Measures

Primary Outcome Measures

1. 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)

2. 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 Outcome Measures

1. 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)

2. 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"

3. 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]

4. 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)

5. 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

6. 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)

7. 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)

8. 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)

9. 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

10. 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

11. 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

12. 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)

13. 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).

14. Mortality due to COVID-19 [Measured over the 6 and 12 months following randomisation]

    Number of deaths due to COVID-19

15. 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).

16. 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

17. 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).

18. 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)

19. 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)

20. 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)

21. 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)

22. 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)

23. 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)

24. 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)

25. Mortality as a consequence of an episode of fever or respiratory illness [Measured over the 12 months following randomisation]

    Number of deaths

26. 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)

27. 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)

28. 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.

29. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St Vincent's Hospital, Sydney	Sydney	New South Wales	Australia	2010
2	Prince of Wales Hospital	Sydney	New South Wales	Australia	2031
3	Sydney Children's Hospital, Randwick	Sydney	New South Wales	Australia	2145
4	The Children's Hospital at Westmead	Sydney	New South Wales	Australia	2145
5	Westmead Hospital	Sydney	New South Wales	Australia	2145
6	Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
7	Women's and Children's Hospital	North Adelaide	South Australia	Australia	5006
8	Royal Children's Hospital	Melbourne	Victoria	Australia	3052
9	Epworth Richmond	Melbourne	Victoria	Australia	3121
10	Monash Health- Monash Medical Centre	Melbourne	Victoria	Australia	3168
11	Fiona Stanley Hospital	Murdoch	Western Australia	Australia	6150
12	Perth Children's Hospital	Perth	Western Australia	Australia	6009
13	Sir Charles Gairdner Hospital	Perth	Western Australia	Australia	6009
14	Fundação de Medicina Tropical Dr Heitor Vieira Dourado (FMT-HVD)	Manaus	Amazonas	Brazil	69040-000
15	Santa Casa Hospital	Campo Grande	Mato Grosso Do Sul	Brazil	79002-230
16	CASSEMS Hospital	Campo Grande	Mato Grosso Do Sul	Brazil	79002-251
17	Federal University of Mato Grosso do Sul	Campo Grande	Mato Grosso Do Sul	Brazil	79070-900
18	Hospital Regional de Mato Grosso do Sul	Campo Grande	Mato Grosso Do Sul	Brazil	79084-180
19	Centro de Estudos da Saúde do Trabalhador e Ecologia Humana	Rio de Janeiro	RJ	Brazil	22780-195
20	Centro de Referência Prof Hélio Fraga	Rio de Janeiro	RJ	Brazil	22780-195
21	Noord West Ziekenhuis	Alkmaar		Netherlands	1815 JD
22	Rijnstate Hospital	Arnhem		Netherlands	6815 AD
23	Amphia Hospital	Breda		Netherlands	4818 CK
24	St Antonius Hospital	Nieuwegein		Netherlands	3435 CM
25	Radboud UMC	Nijmegen		Netherlands	6525 GA
26	University hospital in Utrecht (UMCU)	Utrecht		Netherlands	3584 CX
27	University Hospital German Trias I Pujol	Badalona	Barcelona	Spain	08916
28	Mutua Terrassa Univeristy Hospital	Terrassa	Barcelona	Spain	08221
29	University Hospital Cruces	Barakaldo	Bizkaia	Spain	48903
30	Marqués de Valdecilla University Hospital	Santander		Spain	39008
31	University Hospital Virgen Macarena	Sevilla		Spain	41009
32	Teign Estuary Medical Group	Teignmouth	Devon	United Kingdom	TQ14 8AB
33	Ide Lane Surgery	Alphington	Exeter	United Kingdom	EX2 8UP
34	St Leonard's Practice	St Leonards	Exeter	United Kingdom	EX1 1SB
35	Travel Clinic	Exeter		United Kingdom	EX1 1PR
36	Royal Devon and Exeter NHS Foundation Trust	Exeter		United Kingdom	EX2 5DW

Sponsors and Collaborators

• Murdoch Childrens Research Institute
• Royal Children's Hospital
• Bill and Melinda Gates Foundation

Investigators

• Principal Investigator: Prof Nigel Curtis, Murdoch Children's Research Institute

Study Documents (Full-Text)

• Study Protocol - May 17, 2022
• Statistical Analysis Plan - May 18, 2022
• Informed Consent Form - Sep 14, 2020

More Information

Publications

None provided.

• Responsible Party: Murdoch Childrens Research Institute
• ClinicalTrials.gov Identifier: NCT04327206
• Other Study ID Numbers: 62586; U1111-1256-4104; INV-017302
• First Posted: Mar 31, 2020
• Last Update Posted: Jul 14, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: COVID-19; Coronavirus Infections; Vaccines; BCG Vaccine

Study Results

No Results Posted as of Jul 14, 2022