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COVID-19Phase 3NUEVANCT04632537

BCG Vaccination to Prevent COVID-19

A Phase 3 study testing Tice® BCG (for intravesical use) BCG LIVE strain of the BCG (Merck) vaccine and Preservative-free saline in people with COVID-19, run by Henry M. Jackson Foundation for the Advancement of Military Medicine.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial summary

The current COVID-19 epidemic threatens to overwhelm the capacity of many countries to meet their populations' health care needs. Although several vaccines specific for SARS-CoV-2 have been or are being developed, these require testing in animal and human safety studies and they are unlikely to be available during the… Read more about this study

Who is it for?
Ages 18 to 64 yearsHealthy volunteers can take part
Conditions the study is for
COVID-19
What is being tested?
Tice® BCG (for intravesical use) BCG LIVE strain of the BCG (Merck) vaccine and Preservative-free saline
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
0 participants
Where
No sites listed yet
Study dates
7 Dec 2020to 23 Mar 2021
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 64 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • Physicians, physician assistants, nurse practitioners, nurses, medics, respiratory therapists and other HCWs who are likely to care for patients with COVID-19 illness
  • Eligible for care in DoD facilities (DEERS eligible)*
  • 18-64 years old
  • Willingness to permit review of medical records
  • Women of childbearing potential must be willing to use an effective form of birth control for 30 days post vaccination

Who cannot join

  • Previously (medical history) or currently infected or ill with COVID-19
  • Previous TB disease
  • Fever (>38 C) within the past 24 hours
  • Currently pregnant or breastfeeding or planning on becoming pregnant within 30 days of enrollment
  • Current serious underlying medical conditions including: diabetes mellitus, chronic kidney disease, or any other immunocompromising condition:
  • Known infection by Human Immunodeficiency Virus (HIV)
Show all 19Show fewer
  • History of solid organ or bone marrow transplantation
  • Currently under chemotherapy
  • Currently on any anti-cytokine therapy
  • History of immunodeficiency (including history of anti B cell therapy)
  • Currently taking immunosuppressive drugs
  • Treatment with oral or intravenous steroids, defined as daily doses of 10mg prednisone or equivalent for longer than 3 months
  • Active solid or non-solid malignancy or lymphoma within the past two years
  • Suspicion of active viral or bacterial infection
  • Living with someone HIV+, who is immunocompromised, or is taking an immunosuppressive drug
  • Known allergy to (components of) the BCG vaccine or a serious reaction to prior BCG administration
  • Plan to terminate their employment at the participating health care facility or change duty stations within the next three months
  • Not in possession of a smartphone
  • Current participation in a COVID-19 interventional trial

About this study

Official title: Novel Use of an Existing Vaccine (BCG) Alliance: The NUEVA Trial

The current COVID-19 epidemic threatens to overwhelm the capacity of many countries to meet their populations' health care needs. Although several vaccines specific for SARS-CoV-2 have been or are being developed, these require testing in animal and human safety studies and they are unlikely to be available during the expected peak periods of the growing epidemic. Two groups at especially high risk of infection and disease are front line health care workers working directly with COVID-19 patients and elderly residents of group homes or facilities that provide skilled nursing care to this frail population. Interim measures to protect these groups while we await a high efficacy vaccine are desperately needed.

Based on the capacity of BCG to (1) reduce the incidence of respiratory tract infections in children and adults; (2) exert antiviral effects in experimental models; and (3) reduce viremia in an experimental human model of viral infection, we hypothesize that BCG vaccination may induce (partial) protection against susceptibility to and/or severity of SARS-CoV-2 infection.

Read more

This study will evaluate the efficacy of BCG to reduce risk of infection by SARS-CoV-2 and mitigate COVID-19 disease severity in at risk health care providers.

A phase III randomized controlled trial provides the highest validity to answer this research question. Given the immediate threat of the SARS-CoV-2 epidemic the trial has been designed as a pragmatic study with a highly feasible primary endpoint, which can be continuously measured. This allows for the most rapid identification of a beneficial outcome that would allow other at-risk individuals, including the control population, to also benefit from the intervention if and as soon as it has demonstrated efficacy and safety.

Read the detailed description

This study is a multi-center, prospective, double-blind, randomized placebo-controlled trial to assess the efficacy of intradermal TICE BCG (for intravesical use, Merck) BCG LIVE or placebo vaccine, in reducing the incidence of infection of SARS-CoV2 and severity of COVID-19 disease. This study proposes to examine BCG-induced nonspecific trained immunity to provide protection from SARS-CoV2 among health care workers who are likely to care for patients with COVID-19 illness, 18-64 years of age.

Up to 670 individuals will be screened to enroll 550 participants with a planned 50 person enrollment at USU site, 300 persons at Darnall Medical Center (CRDMC) and 200 persons at Brooke Army Medical Center (BAMC), resulting in 275 receiving BCG vaccine and 275 receiving placebo. To account for attrition prior to vaccination we will enroll up to 70 at USU, up to 350 at CRDMC and up to 250 at BAMC.

There are three phases in which research procedures will be completed: (1) initial screening for eligibility, consent, baseline testing; (2) enrollment, randomization, if pertains- prior to vaccination research blood draw for peripheral blood mononuclear cells (PBMC), and immunization with study vaccine (BCG or placebo); and (3) follow-up screening and testing.

Participants will be followed to assess whether infection with SARS-CoV-2 occurs:

Participants will complete intermittent surveys via an electronic system every 2 weeks to assess the presence of any flu-like symptom. Any positive response on the survey will trigger a nasopharyngeal swab to be collected to test for COVID-19 via rt-PCR.

All participants, regardless of survey responses, will have serology (4mL SST tube) for COVID-19 tested at monthly intervals during the 6 month follow-up period or until a positive test result occurs.

If a participant completes the follow-up period and does not test positive for COVID disease, study participation is complete.

If a participant does test positive for COVID-19 disease at any point during follow-up, disease status will be ascertained for up to two months from the time of positive test or until an outcome is available through one of the following mechanisms:

(1) an electronic survey if not admitted to the hospital, including questions about the number of days ill, daily fever, and other symptoms; or (2) if admitted to the hospital, ordinal outcomes for disease severity will be extracted from the hospital's medical records system for the 2 month period of highest acuity. Participants will have a final study visit after hospitalization when cleared for outpatient follow up.

During the first 6 weeks of follow-up post vaccination, all participants will be asked about any adverse events; thereafter, participants will report vaccine-related and solicited adverse events (AE), as well as unsolicited AEs through the electronic survey.

Conditions
COVID-19
Being tested
Tice® BCG (for intravesical use) BCG LIVE strain of the BCG (Merck) vaccine, Preservative-free saline
Keywords
COVID-19, BCG, vaccine, clinical trial
Medical subject headings
COVID-19

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Tice® BCG (for intravesical use) BCG LIVE strain of the BCG (Merck) vaccineDrug

    Tice® BCG (for intravesical use) BCG LIVE strain of the BCG (Merck) vaccine will be diluted in preservative-free saline and given intradermally (0.1mL) in the deltoid area.

  • Preservative-free salineDrug

    Placebo will be administered in an intradermal route in the same location as the BCG vaccines: upper arm. Placebo will comprise 0.1 mL of the diluent (preservative-free saline) to ensure the same quantity and same color as the resuspended BCG vaccine, rendering the two indistinguishable.

Study groups in NCT04632537
Study groupRoleWhat they receive
TICE BCG (for intravesical use, Merck) BCG LIVEActive comparatorParticipants randomized to the BCG arm will receive Tice® BCG (for intravesical use) BCG LIVE is a live freeze-dried vaccine made from an attenuated strain of Mycobacterium bovis. The freeze-dried vaccine will be delivered in vials, each containing 1 to 8 x108 colony forming units (CFU). Tice® BCG (for intravesical use) BCG LIVE will be reconstituted in ~5 mL of preservative-free saline, as needed for yielding 2- x107 CFU/ mL. [34] Administration of 0.1 mL will contain 2x106 CFU, which accounts for approximately 0.1 mg of the attenuated Mycobacterium bovis. Administration of 0.1 mL of diluted vaccine will be given per dose, intradermally. A sterile tuberculin 1mL syringe and sterile fine short needle (25 or 26 gauge with 3/8-3/4 length), will be used for each injection. The injection should be made slowly after inserting the needle ~2 mm into the superficial layer of the dermis of the upper arm (usually deltoid area), to make a symmetrical superficial bleb.
Receives: Drug: Tice® BCG (for intravesical use) BCG LIVE strain of the BCG (Merck) vaccine
placebo vaccinePlacebo comparatorPlacebo will be administered in an intradermal route in the same location as the BCG vaccines: upper arm. Placebo will comprise 0.1 mL of the diluent (preservative-free saline) to ensure the same quantity and same color as the resuspended BCG vaccine, rendering the two indistinguishable.
Receives: Drug: Preservative-free saline

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Incidence of symptomatic rt-PCR-confirmed SARS-CoV-2 infection

    The primary outcome measure is the development of symptomatic COVID 19 infections. We will use the Cox proportional-hazards model to calculate hazard ratios for the development of COVID-19. This will be reported as the incidence of rt-PCR-confirmed symptomatic SARS-CoV-2 infection following BCG vaccination compared to that following placebo, starting from 3 days post-vaccination through 6 months.

    Measured: 6 months

Secondary outcomes (4)

  1. incidence of Serology-confirmed infection with SARS-CoV-2

    The secondary outcome measure is the development of Serology-confirmed infection with SARS-CoV-2. We will use the Cox proportional-hazards model to calculate hazard ratios for the development of COVID-19. This will be reported as the incidence of serology-confirmed SARS-CoV-2 following BCG vaccination compared to that following placebo, starting from 3 days post vaccination through 6 months.

    Measured: 6 months

  2. severity of COVID-19 disease

    In individuals who test positive for COVID-19, the proportion with severe disease following BCG vaccination compared to placebo, as defined by the following necessary care levels: non- hospital care; patient hospitalized but no oxygen required; hospitalized and oxygen required; patient treated in intensive care and/or on mechanical ventilation; patient died.Additional WHO severity indicators of severe pneumonia, respiratory failure, sepsis, septic shock will also be included.

    Measured: 6 months

  3. symptomatic respiratory infection

    Incidence of self-reported symptomatic respiratory infections following BCG vaccination compared to that following placebo, starting from 3 days post-vaccination through 6 months.

    Measured: 6 months

  4. effect of prior adult immunization with other vaccines associated with trained immunity

    rates of 1) all cause respiratory infection 2) symptomatic COVID- 19, 3) serology-confirmed SARS-CoV-2 infection in health care workers.

    Measured: 6 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Nov 2020
  2. Study start7 Dec 2020
  3. Primary completion23 Mar 2021
  4. Study completion23 Mar 2021

Why it stopped: Due to funding - project never enrolled

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04632537
Sponsor's protocol ID
USUHS.2020-062
Acronym
NUEVA
Status last verified
Mar 2021
First submitted
4 Nov 2020
Last updated
26 Mar 2021
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • World Health Organization. Coronavirus disease 2019 (COVID-19): Situation Report - 23. COVID-19 Situational Reports (2020). Accessed on April 1, 2020 at: https://www.who.int/docs/default- source/coronaviruse/situation-reports/20200212-sitrep-23-nCoV.pdf?sfvrsn=41e9fb78_4

  • Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24.

    PubMed 31986264

  • Chang D, Xu H, Rebaza A, Sharma L, Dela Cruz CS. Protecting health-care workers from subclinical coronavirus infection. Lancet Respir Med. 2020 Mar;8(3):e13. doi: 10.1016/S2213-2600(20)30066-7. Epub 2020 Feb 13. No abstract available.

    PubMed 32061333

  • Zhang J, Zhou L, Yang Y, Peng W, Wang W, Chen X. Therapeutic and triage strategies for 2019 novel coronavirus disease in fever clinics. Lancet Respir Med. 2020 Mar;8(3):e11-e12. doi: 10.1016/S2213-2600(20)30071-0. Epub 2020 Feb 13. No abstract available.

    PubMed 32061335

  • Chou R, Dana T, Buckley DI, Selph S, Fu R, Totten AM. Epidemiology of and Risk Factors for Coronavirus Infection in Health Care Workers: A Living Rapid Review. Ann Intern Med. 2020 Jul 21;173(2):120-136. doi: 10.7326/M20-1632. Epub 2020 May 5.

    PubMed 32369541

  • Rivett L, Sridhar S, Sparkes D, Routledge M, Jones NK, Forrest S, Young J, Pereira-Dias J, Hamilton WL, Ferris M, Torok ME, Meredith L; CITIID-NIHR COVID-19 BioResource Collaboration; Curran MD, Fuller S, Chaudhry A, Shaw A, Samworth RJ, Bradley JR, Dougan G, Smith KG, Lehner PJ, Matheson NJ, Wright G, Goodfellow IG, Baker S, Weekes MP. Screening of healthcare workers for SARS-CoV-2 highlights the role of asymptomatic carriage in COVID-19 transmission. Elife. 2020 May 11;9:e58728. doi: 10.7554/eLife.58728.

    PubMed 32392129

  • CDC COVID-19 Response Team. Characteristics of Health Care Personnel with COVID-19 - United States, February 12-April 9, 2020. MMWR Morb Mortal Wkly Rep. 2020 Apr 17;69(15):477-481. doi: 10.15585/mmwr.mm6915e6.

    PubMed 32298247

  • Nguyen LH, Drew DA, Graham MS, Joshi AD, Guo CG, Ma W, Mehta RS, Warner ET, Sikavi DR, Lo CH, Kwon S, Song M, Mucci LA, Stampfer MJ, Willett WC, Eliassen AH, Hart JE, Chavarro JE, Rich-Edwards JW, Davies R, Capdevila J, Lee KA, Lochlainn MN, Varsavsky T, Sudre CH, Cardoso MJ, Wolf J, Spector TD, Ourselin S, Steves CJ, Chan AT; COronavirus Pandemic Epidemiology Consortium. Risk of COVID-19 among front-line health-care workers and the general community: a prospective cohort study. Lancet Public Health. 2020 Sep;5(9):e475-e483. doi: 10.1016/S2468-2667(20)30164-X. Epub 2020 Jul 31.

    PubMed 32745512

  • Wang X, Ferro EG, Zhou G, Hashimoto D, Bhatt DL. Association Between Universal Masking in a Health Care System and SARS-CoV-2 Positivity Among Health Care Workers. JAMA. 2020 Aug 18;324(7):703-704. doi: 10.1001/jama.2020.12897.

    PubMed 32663246

  • Ritz N, Hanekom WA, Robins-Browne R, Britton WJ, Curtis N. Influence of BCG vaccine strain on the immune response and protection against tuberculosis. FEMS Microbiol Rev. 2008 Aug;32(5):821-41. doi: 10.1111/j.1574-6976.2008.00118.x. Epub 2008 Jul 9.

    PubMed 18616602

  • Abubakar I, Pimpin L, Ariti C, Beynon R, Mangtani P, Sterne JA, Fine PE, Smith PG, Lipman M, Elliman D, Watson JM, Drumright LN, Whiting PF, Vynnycky E, Rodrigues LC. Systematic review and meta-analysis of the current evidence on the duration of protection by bacillus Calmette-Guerin vaccination against tuberculosis. Health Technol Assess. 2013 Sep;17(37):1-372, v-vi. doi: 10.3310/hta17370.

    PubMed 24021245

  • Walk J, de Bree LCJ, Graumans W, Stoter R, van Gemert GJ, van de Vegte-Bolmer M, Teelen K, Hermsen CC, Arts RJW, Behet MC, Keramati F, Moorlag SJCFM, Yang ASP, van Crevel R, Aaby P, de Mast Q, van der Ven AJAM, Stabell Benn C, Netea MG, Sauerwein RW. Outcomes of controlled human malaria infection after BCG vaccination. Nat Commun. 2019 Feb 20;10(1):874. doi: 10.1038/s41467-019-08659-3.

    PubMed 30787276

  • Koeken VACM, Verrall AJ, Netea MG, Hill PC, van Crevel R. Trained innate immunity and resistance to Mycobacterium tuberculosis infection. Clin Microbiol Infect. 2019 Dec;25(12):1468-1472. doi: 10.1016/j.cmi.2019.02.015. Epub 2019 Feb 23.

    PubMed 30807849

  • Suliman S, Geldenhuys H, Johnson JL, Hughes JE, Smit E, Murphy M, Toefy A, Lerumo L, Hopley C, Pienaar B, Chheng P, Nemes E, Hoft DF, Hanekom WA, Boom WH, Hatherill M, Scriba TJ. Bacillus Calmette-Guerin (BCG) Revaccination of Adults with Latent Mycobacterium tuberculosis Infection Induces Long-Lived BCG-Reactive NK Cell Responses. J Immunol. 2016 Aug 15;197(4):1100-1110. doi: 10.4049/jimmunol.1501996. Epub 2016 Jul 13.

    PubMed 27412415

  • 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.

    PubMed 29996082

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Tice® BCG (for intravesical use) BCG LIVE strain of the BCG (Merck) vaccine and Preservative-free saline in people with COVID-19, run by Henry M. Jackson Foundation for the Advancement of Military Medicine.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 26 Mar 2021. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of symptomatic rt-PCR-confirmed SARS-CoV-2 infection (time frame: 6 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04632537, which also lists 41 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Mar 2021.

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BCG Vaccination to Prevent COVID-19 (NCT04632537) | AzTrials