BCG to Reduce Absenteeism Among Health Care Workers During the COVID-19 Pandemic

NCT04641858 | Completed Phase 4 DMC

• 1 other identifier: BCG-COVID-RCT
• Study Type: interventional
• Target: 668
• Locations: 2 countries
• Sites: 2

Brief Summary

The COVID-19 pandemic challenges available hospital capacity. Strategies to protect health care workers (HCW) are desperately needed. Bacille Calmette- Guérin (BCG) has protective non-specific effects against other infections; a plausible immunological mechanism has been identified in terms of "trained innate immunity". The primary objective of the study is to evaluate whether BCG can reduce unplanned absenteeism due to illness among HCW during the COVID-19 pandemic. Secondary objectives are to reduce the number of HCW that are infected with COVID-19, reduce hospital admissions for HCW and to improve the capacity for clinical research. Design: Single-blind, parallel-group placebo-controlled multi-centre block randomized trial including a total of 1050 HCW. The study sites will be the Manhiça hospital in Mozambique, Central Hospital Dr. Agostinho Neto and Central Hospital Dr. Baptista de Sousa in Cape Verde and Hospital Nacional Simão Mendes and other hospitals in the capital Bissau in Guinea-Bissau. Population: HCW (nurses/physicians/others) ≥18 years. Intervention: Block randomization 1:1 to intradermal standard dose (0.1 ml) of BCG vaccine or placebo (saline). Endpoints: Primary: Days of unplanned absenteeism due to illness. Secondary: Days of absenteeism because of documented COVID-19; cumulative incidence of infectious disease hospitalizations. Follow-up: mobile phone interviews every second week, regarding symptoms, absenteeism and causes, COVID-19 testing (if done) and their results. Perspectives: If BCG can reduce HCW absenteeism it has global implications. The intervention can quickly be scaled up all over the world.

Conditions

Covid19; Morbidity; Absenteeism

Keywords

Innate immune training; Non-specific effects of BCG; Heterologous effects

Outcome Measures

Primary Outcomes (1)

• Days of unplanned absenteeism due to illness

  Unplanned absenteeism is defined by being absent from work due to causes other than holidays, parental leave, and other planned leaves, family assistance (including mourning leave) and quarantine measures.

  6 months after inclusion

Secondary Outcomes (3)

• Days of unplanned absenteeism due to documented COVID-19

  6 months after inclusion

• Cumulative incidence of hospital admissions due to illness (minus accidents).

  6 months after inclusion

• Death

  6 months after inclusion

Other Outcomes (7)

• Hospitalisation for COVID-19

  6 months after inclusion

• Hospitalisation besides COVID-19

  6 months after inclusion

• Time to hospitalisation

  6 months after inclusion

Study Arms (2)

BCG-Denmark

ACTIVE COMPARATOR

Participants that are randomized in the active arm will receive an adult 0.1 ml dose of BCG vaccine (BCG-Denmark, AJ Vaccines) in the skin covering the right upper deltoid muscle. Each 0.1 ml vaccine contains between 200000 to 800000 colony forming units of the live attenuated strain of Mycobacterium bovis (BCG), Danish strain 1331.

Biological: BCG-Denmark

Control

PLACEBO COMPARATOR

Placebo will be 0.1 ml sterile 0.9 % NaCl, which has a similar color and appearance as the resuspended BCG vaccine.

Biological: Saline

Interventions

BCG-Denmark BIOLOGICAL

Participants randomized to receive BCG will receive one 0.1 ml dose of Mycobacterium bovis BCG live attenuated BCG-Denmark vaccine (AJ Vaccines, Copenhagen, Denmark) by intradermal injection in the left deltoid region.

BCG-Denmark

Saline BIOLOGICAL

Participants randomized to the control group will receive one 0.1 ml dose sterile 0.9 % NaCl by intradermal injection in the right deltoid region.

Control

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• health care worker (physician, nurse, or other) based at one of the research hospitals.
• age ≥18 years

You may not qualify if:

• known allergy to (components of) BCG or serious adverse events to prior BCG administration;
• known previous, active or latent infection with Mycobacterium tuberculosis or other mycobacterial species
• fever (\>38 C) within past 24 hours;
• previous confirmed COVID-19 (positive test - PCR or antibody);
• suspicion of active viral or bacterial infection
• severely immunocompromised subjects
• self-reported HIV infection
• self-reported pregnancy;
• active solid or non-solid malignancy or lymphoma within the prior two years;
• contraindications for live attenuated vaccine administration.
• not having a mobile phone.

Sponsors & Collaborators

• University of Southern Denmark: lead
• Institute of Hygiene and Tropical Medicine, NOVA University, Lisbon, Portugal: collaborator
• University of Cape Verde, Praia, Cape Verde: collaborator
• National Institute of Public Health of Cape Verde, Praia, Cape Verde: collaborator
• Centro de Investigacao em Saude de Manhica: collaborator
• European and Developing Countries Clinical Trials Partnership (EDCTP): collaborator
• Bandim Health Project, Bissau, Guinea-Bissau: collaborator

Study Sites (2)

Bandim Health Project

Bissau, SAB, 1004, Guinea-Bissau

Location

Manhiça Health Research Centre

Manhiça, Maputo Province, 1929, Mozambique

Location

Related Publications (15)

• Aaby P, Kollmann TR, Benn CS. Nonspecific effects of neonatal and infant vaccination: public-health, immunological and conceptual challenges. Nat Immunol. 2014 Oct;15(10):895-9. doi: 10.1038/ni.2961.

  PMID: 25232810 BACKGROUND

• Aaby P, Benn CS. Developing the concept of beneficial non-specific effect of live vaccines with epidemiological studies. Clin Microbiol Infect. 2019 Dec;25(12):1459-1467. doi: 10.1016/j.cmi.2019.08.011. Epub 2019 Aug 23.

  PMID: 31449870 BACKGROUND

• Benn CS, Fisker AB, Rieckmann A, Sorup S, Aaby P. Vaccinology: time to change the paradigm? Lancet Infect Dis. 2020 Oct;20(10):e274-e283. doi: 10.1016/S1473-3099(19)30742-X. Epub 2020 Jul 6.

  PMID: 32645296 BACKGROUND

• Aaby P, Roth A, Ravn H, Napirna BM, Rodrigues A, Lisse IM, Stensballe L, Diness BR, Lausch KR, Lund N, Biering-Sorensen S, Whittle H, Benn CS. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis. 2011 Jul 15;204(2):245-52. doi: 10.1093/infdis/jir240.

  PMID: 21673035 BACKGROUND

• Biering-Sorensen S, Aaby P, Lund N, Monteiro I, Jensen KJ, Eriksen HB, Schaltz-Buchholzer F, Jorgensen ASP, Rodrigues A, Fisker AB, Benn CS. Early BCG-Denmark and Neonatal Mortality Among Infants Weighing <2500 g: A Randomized Controlled Trial. Clin Infect Dis. 2017 Oct 1;65(7):1183-1190. doi: 10.1093/cid/cix525.

  PMID: 29579158 BACKGROUND

• Higgins JP, Soares-Weiser K, Lopez-Lopez JA, Kakourou A, Chaplin K, Christensen H, Martin NK, Sterne JA, Reingold AL. Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ. 2016 Oct 13;355:i5170. doi: 10.1136/bmj.i5170.

  PMID: 27737834 BACKGROUND

• Rieckmann A, Villumsen M, Sorup S, Haugaard LK, Ravn H, Roth A, Baker JL, Benn CS, Aaby P. Vaccinations against smallpox and tuberculosis are associated with better long-term survival: a Danish case-cohort study 1971-2010. Int J Epidemiol. 2017 Apr 1;46(2):695-705. doi: 10.1093/ije/dyw120.

  PMID: 27380797 BACKGROUND

• Wardhana, Datau EA, Sultana A, Mandang VV, Jim E. The efficacy of Bacillus Calmette-Guerin vaccinations for the prevention of acute upper respiratory tract infection in the elderly. Acta Med Indones. 2011 Jul;43(3):185-90.

  PMID: 21979284 BACKGROUND

• Nemes E, Geldenhuys H, Rozot V, Rutkowski KT, Ratangee F, Bilek N, Mabwe S, Makhethe L, Erasmus M, Toefy A, Mulenga H, Hanekom WA, Self SG, Bekker LG, Ryall R, Gurunathan S, DiazGranados CA, Andersen P, Kromann I, Evans T, Ellis RD, Landry B, Hokey DA, Hopkins R, Ginsberg AM, Scriba TJ, Hatherill M; C-040-404 Study Team. Prevention of M. tuberculosis Infection with H4:IC31 Vaccine or BCG Revaccination. N Engl J Med. 2018 Jul 12;379(2):138-149. doi: 10.1056/NEJMoa1714021.

  PMID: 29996082 BACKGROUND

• Netea MG, Joosten LA, Latz E, Mills KH, Natoli G, Stunnenberg HG, O'Neill LA, Xavier RJ. Trained immunity: A program of innate immune memory in health and disease. Science. 2016 Apr 22;352(6284):aaf1098. doi: 10.1126/science.aaf1098. Epub 2016 Apr 21.

  PMID: 27102489 BACKGROUND

• Arts RJW, Moorlag SJCFM, Novakovic B, Li Y, Wang SY, Oosting M, Kumar V, Xavier RJ, Wijmenga C, Joosten LAB, Reusken CBEM, Benn CS, Aaby P, Koopmans MP, Stunnenberg HG, van Crevel R, Netea MG. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host Microbe. 2018 Jan 10;23(1):89-100.e5. doi: 10.1016/j.chom.2017.12.010.

  PMID: 29324233 BACKGROUND

• Benn CS, Fisker AB, Whittle HC, Aaby P. Revaccination with Live Attenuated Vaccines Confer Additional Beneficial Nonspecific Effects on Overall Survival: A Review. EBioMedicine. 2016 Aug;10:312-7. doi: 10.1016/j.ebiom.2016.07.016. Epub 2016 Jul 15.

  PMID: 27498365 BACKGROUND

• Roth AE, Benn CS, Ravn H, Rodrigues A, Lisse IM, Yazdanbakhsh M, Whittle H, Aaby P. Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau. BMJ. 2010 Mar 15;340:c671. doi: 10.1136/bmj.c671.

  PMID: 20231251 BACKGROUND

• Biot C, Rentsch CA, Gsponer JR, Birkhauser FD, Jusforgues-Saklani H, Lemaitre F, Auriau C, Bachmann A, Bousso P, Demangel C, Peduto L, Thalmann GN, Albert ML. Preexisting BCG-specific T cells improve intravesical immunotherapy for bladder cancer. Sci Transl Med. 2012 Jun 6;4(137):137ra72. doi: 10.1126/scitranslmed.3003586.

  PMID: 22674550 BACKGROUND

• Hatherill M, Geldenhuys H, Pienaar B, Suliman S, Chheng P, Debanne SM, Hoft DF, Boom WH, Hanekom WA, Johnson JL. Safety and reactogenicity of BCG revaccination with isoniazid pretreatment in TST positive adults. Vaccine. 2014 Jun 30;32(31):3982-8. doi: 10.1016/j.vaccine.2014.04.084. Epub 2014 May 9.

  PMID: 24814553 BACKGROUND

MeSH Terms

Conditions

COVID-19

Interventions

Sodium Chloride

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Christine Stabell Benn, Professor

  University of Southern Denmark

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: Participants will be blinded to treatment. The physicians administering the BCG vaccine or placebo will not be blinded. Those assessing outcomes will be blinded to the randomization allocation. In case of serious adverse events, the participant can be unblinded after consultation with the coordinating PI or sponsor.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Multi-center randomized placebo-controlled trial

Study Record Dates

• First Submitted: November 22, 2020
• First Posted: November 24, 2020
• Study Start: December 3, 2020
• Primary Completion: July 13, 2022
• Study Completion: July 13, 2022
• Last Updated: November 3, 2022

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: When follow-up has been completed and the dataset have been closed.
• Access Criteria: Non-identifiable individual data can be shared on the basis of a data sharing proposal sent to ifronteira@ihmt.unl.pt

Locations

GU (1); MO (1)