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BCG Vaccination to Prevent COVID-19 (NUEVA)

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ClinicalTrials.gov Identifier: NCT04632537
Recruitment Status : Recruiting
First Posted : November 17, 2020
Last Update Posted : January 12, 2021
Sponsor:
Collaborators:
Harvard Medical School
Uniformed Services University of the Health Sciences
United States Department of Defense
Immunization HealthCare Division, Defense Health Agency
Information provided by (Responsible Party):
Henry M. Jackson Foundation for the Advancement of Military Medicine

Tracking Information
First Submitted Date  ICMJE November 4, 2020
First Posted Date  ICMJE November 17, 2020
Last Update Posted Date January 12, 2021
Actual Study Start Date  ICMJE December 7, 2020
Estimated Primary Completion Date November 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 16, 2020)		 Incidence of symptomatic rt-PCR-confirmed SARS-CoV-2 infection [ Time Frame: 6 months ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 16, 2020)
  • incidence of Serology-confirmed infection with SARS-CoV-2 [ Time Frame: 6 months ]
    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.
  • severity of COVID-19 disease [ Time Frame: 6 months ]
    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.
  • symptomatic respiratory infection [ Time Frame: 6 months ]
    Incidence of self-reported symptomatic respiratory infections following BCG vaccination compared to that following placebo, starting from 3 days post-vaccination through 6 months.
  • effect of prior adult immunization with other vaccines associated with trained immunity [ Time Frame: 6 months ]
    rates of 1) all cause respiratory infection 2) symptomatic COVID- 19, 3) serology-confirmed SARS-CoV-2 infection in health care workers.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE BCG Vaccination to Prevent COVID-19
Official Title  ICMJE Novel Use of an Existing Vaccine (BCG) Alliance: The NUEVA Trial
Brief 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 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.

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.
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
Condition  ICMJE COVID-19
Intervention  ICMJE
  • Drug: Tice® BCG (for intravesical use) BCG LIVE strain of the BCG (Merck) vaccine
    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.
  • Drug: Preservative-free saline
    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 Arms  ICMJE
  • Active Comparator: TICE BCG (for intravesical use, Merck) BCG LIVE
    Participants 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.
    Intervention: Drug: Tice® BCG (for intravesical use) BCG LIVE strain of the BCG (Merck) vaccine
  • Placebo Comparator: placebo vaccine
    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.
    Intervention: Drug: Preservative-free saline
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 16, 2020)		 550
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 2023
Estimated Primary Completion Date November 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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)
    • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 64 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Marianne Spevak, BSHS 2406942067 mspevak@hjf.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04632537
Other Study ID Numbers  ICMJE USUHS.2020-062
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Henry M. Jackson Foundation for the Advancement of Military Medicine
Study Sponsor  ICMJE Henry M. Jackson Foundation for the Advancement of Military Medicine
Collaborators  ICMJE
  • Harvard Medical School
  • Uniformed Services University of the Health Sciences
  • United States Department of Defense
  • Immunization HealthCare Division, Defense Health Agency
Investigators  ICMJE
Principal Investigator: Jeffrey R Livezey, MD Uniformed Services University of the Health Sciences
Study Chair: Naomi E Aronson Uniformed Services University of the Health Sciences
PRS Account Henry M. Jackson Foundation for the Advancement of Military Medicine
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP