BCG Vaccine for Health Care Workers as Defense Against COVID 19 (BADAS)

• ClinicalTrials.gov Identifier: NCT04348370
• Recruitment Status: Active, not recruiting
• First Posted: April 16, 2020
• Last Update Posted: October 19, 2022
• Sponsor: Texas A&M University
• Collaborators: Baylor College of Medicine; M.D. Anderson Cancer Center; Cedars-Sinai Medical Center; Harvard University
• Information provided by (Responsible Party): Texas A&M University

Study Description

Brief Summary:

SARS-CoV-2 spreads rapidly throughout the world. A large epidemic would seriously challenge the available hospital capacity, and this would be augmented by infection of healthcare workers (HCW). Strategies to prevent infection and disease severity of HCW are, therefore, desperately needed to safeguard continuous patient care. Bacille Calmette-Guérin (BCG) is a vaccine against tuberculosis, with protective non-specific effects against other respiratory tract infections in in vitro and in vivo studies, and reported morbidity and mortality reductions as high as 70%. Furthermore, in our preliminary analysis, areas with existing BCG vaccination programs appear to have lower incidence and mortality from COVID191. The investigators hypothesize that BCG vaccination can reduce HCW infection and disease severity during the epidemic phase of SARS-CoV-2.

Condition or disease	Intervention/treatment	Phase
Coronavirus; Coronavirus Infection; Coronavirus as the Cause of Diseases Classified Elsewhere	Biological: BCG Vaccine; Biological: Placebo Vaccine	Phase 4

Detailed Description:

Study design: A placebo-controlled adaptive multi-center randomized controlled trial.

Study population: High risk HCW with direct patient contacts, defined as physician assistants, respiratory therapists, nurses, physicians or other HCWs working at emergency rooms, ICUs and in locations within hospitals where COVID-infected patients are treated.

Intervention: Participants will be randomized between intradermal administration of BCG vaccine or placebo in a 1:1 ratio.

Recruitment, Randomization, treatment allocation, and blinding

A standardized, IRB approved email will be sent to department chairs describing the study. A research coordinator will reach out to interested participants via phone with the help of an IRB-approved verbal script to introduce the study, confirm eligibility and provide further instructions on how to access and sign the IRB-approved ICD via REDCap using their own electronic devices. It is important that the investigators obtain the consent via REDCAp to a) avoid direct person-to-person contact and comply with social distancing imposed recommendations, and b) minimize the waste of reconstituted BCG by allowing the research personnel to schedule vaccinations in a controlled fashion. Patient registration into the trial will happen immediately after consent has been provided and will involve entering of baseline information into an electronic data capture system (RedCap).

Once the eligibility is confirmed and the ICD signed by the participant and stored in REDCap, the research coordinator will randomize the participant and communicate the treatment assignment to the nurse administering the vaccination. The nurse will subsequently assign an appointment and communicate date and time of vaccination with the participant. All eligible participants will receive intradermal injections of BCG:placebo in a 1:1 ratio.

Both, participants and investigators will be blinded to the treatment assignments during the study. However, in case of an emergency where it is important to know the treatment received, the investigator and/or participant can reach out to the unblinded study personnel who will provide the unblinded data. All participants will receive their treatment allocation at the end of the study, after the data analysis is finalized.

Unblinded personnel will not be involved in the collection and analysis of study data other than the baseline eligibility criteria.

The end of the study is defined as the last patient's last entry in the electronic data capture system.

Informed Consent and Eligibility

The following types of procedures will be conducted as indicated below:

Medical history will be obtained from patient medical record/clinical chart. Informed Consent will be obtained to access these records. When information cannot be obtained or is not available from the patient medical record/clinical chart, it will be obtained via patient interview. Physical examination will be conducted solely to look for existing BCG vaccination scars.

Symptom evaluation will be conducted via an electronic survey administered to participants every 1-3 days.

HIV and pregnancy will be collected as self-reported information. If unknown, a urine pregnancy test will be performed.

Nasopharyngeal, oral and/ or rectal swabs will be collected for rt-PCR test for SARS-CoV2 infection if a study develops symptoms consistent with Covid-19.

If a participant does not know their PPD/IGRA status from within the last 24 months (all health care providers should have this information), an IGRA can be performed to evaluate eligibility.

Study participants have the option of donating blood via phlebotomy (for serological test for Covid-19 disease and PBMCs for immune correlates) or providing a fingerstick and dried blood spot (for serologic test for Covid-19).

Data will be collected at four time points/periods: (1) after consent, (2) at baseline, (3) during follow-up period, and (4) at study end.

Data to be collected during screening includes medical history, physical exam results, results of rt-PCR and serological test results.

Data to be collected during baseline enrollment includes eligibility confirmation, demographic information, risk factors, randomization assignment, confirmation of BCG vaccination/placebo, any immediate reactions to BCG vaccination/placebo.

Data to be collected during follow-up includes intermittent surveys about the presence of flu-like symptoms, rt-PCR test results if done, serological test results, if testing positive for Covid-19 information regarding their disease course, and disease outcome status.

THE FOLLOWING IS COLLECTED AFTER CONSENT IS OBTAINED:

Date of signed Informed Consent Form

Role in hospital

Department in hospital

rt-PCR test for SARS-CoV2 result

Serological test for Covid-19 result

Number of BCG scars (by visual/physical examination)

Medical history*

Previous PPD and IGRA test results

History of TB disease

History of previous HIV testing

Urine Pregnancy test result (if applicable)

Plans of pregnancy in 30 days

Plan to stop working in 3 months/ leave facility in 6 months

Current diabetes mellitus

Current chronic kidney disease

Currently taking immunosuppressive drugs

Living with someone with HIV, immunocompromised, taking immunosuppressive drug

Chemotherapy in past 3 months

History of organ/bone marrow transplant

Access to smartphone

BASELINE DATA COLLECTION/PROCEDURES

The following procedures will be conducted and data collected as indicated below:

A questionnaire to obtain information about age, sex, demographic information, who they live with, smoking status, any current medications they are on, and other comorbidities

Participants will then be randomized to either receive a single dose of BCG vaccination or placebo.

BCG vaccination or placebo will be administered.

Eligibility screening data will carry forward into the trial.

The following additional data points will be collected:

Age

Sex

Race

Ethnicity

Nationality

Who they live with

Height

Weight

Smoking status/tobacco use

Alcohol use

Current list of medications

Current list of comorbidities

History of diabetes mellitus

History of hypertension

History of stroke

History of kidney disease

History of COPD

Randomization assignment

BCG/placebo administered

FOLLOW-UP PROCEDURES AND DATA COLLECTION:

Participants will be followed to assess whether they get infected with SARS-CoV2:

Participants will complete intermittent surveys via an electronic system every 1-3 days to assess the presence of any flu-like symptom, including sore throat, fever, headache, malaise, and cough. Note that this is part of routine surveillance for Covid-19 in health workers at the United States site. Consent forms will ask for consent to access this survey information.

Any positive response on the survey will trigger a nasopharyngeal, oral and/ or rectal swab to be collected to test for Covid-19 via rt-PCR

All participants, regardless of survey responses, will have serology for Covid-19 tested at 4 week intervals during the follow-up period (6 months)

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

If a participant does test positive for disease, their disease status will be ascertained for up to two months or until an outcome is available through one of the following mechanisms: (1) an electronic survey if they are not admitted to the hospital, including questions about the number of days they are ill, daily fever, and other symptoms; or (2) (2) if they are admitted to the hospital, ordinal outcomes for disease severity will be extracted from the hospital¿s electronic medical records system.

During the first week of follow-up, all participants will actively be asked about any adverse events; thereafter, participants will report unsolicited AEs through the electronic survey. Vaccine related adverse events will be graded using the FDA guidance (https://www.fda.gov/media/73679/download) and noted using WHO-recommended Adverse event following Immunization forms (AEFI; https://vaccine-safety-training.org/classification-of-aefis.html).

Participants will have the option of donating 12 mL of blood for plasma (serology) and PBMCs for secondary analysis of immune correlates and for future analysis based on covid19-specific IgM and IgG. If they do not donate 12mL of blood, a fingerstick will be required for baseline COVID19 serology.

Dried Blood Spot (DBS): all participants are HCWs and will self-collect DBS samples at week 4, 8, 12, 16, 20 and 24. Envelopes to store the DBS are provided upon enrollment and can be dropped off at work and picked up by study coordinators to minimize HCW distractions.

COVID specific RNA is found in stool for ~21 days when an individual develops infection (https://doi.org/10.1038/s41586-020-2196-x). Participants will have the option of collecting stool swabs monthly if they are asymptomatic or weekly if they develop symptoms. Nucleic acid testing will be performed in retrospect to support secondary objectives.

If participants develop symptoms consistent with COVD19, will be PCR tested for COVID19. They will be given the option of donating 12 mL of blood for plasma and PBMCs 2 weeks after symptoms resolve.

Week 12 (+/- 2 Weeks), participants will be given the option to donate 12 mL of blood for plasma and PBMCs for secondary analysis of immune correlates and for future secondary analysis based on covid-specific IgM and IgG.

Week 24 (+/- 2 Weeks), participants will be given the option to donate 12 mL of blood for plasma and

PBMCs for secondary analysis of immune correlates and for future secondary analysis based on covid-specific IgM and IgG.

Except for the administration of BCG vaccine or placebo and the above mentioned DBS and phlebotomy, participants will undergo no invasive procedures for study purposes.

The following data points will be collected during the follow-up period AND AT

END OF STUDY TIMEPOINT:

Sore throat (collected at multiple time points)

Fever (collected at multiple time points)

Headache (collected at multiple time points)

Malaise (collected at multiple time points)

Cough (collected at multiple time points)

rt-PCR test for SARS-CoV2 result (as indicated)

Serological test for Covid-19 result (every 2 weeks)

Number of days ill

Daily fever

Other Covid-19 symptoms

Admitted to hospital

Required oxygen

Treated in intensive care

Required ventilation

Death

Severe pneumonia

Respiratory failure

Acute respiratory distress syndrome

Sepsis

Septic shock

*Already being collected as part of routine surveillance of health care workers. Will request access to this information in Informed Consent Form.

Subjects can leave the study at any time for any reason if they wish to do so without any consequences. The investigator can decide to withdraw a subject from the study for urgent medical reasons. Participants who received placebo will be unblinded at the end of the study and pending a recommendation by the DSMB, they will be offered the option of receiving the BCG intervention.

A participant will only be replaced in case of withdrawal before the administration of BCG vaccine/placebo.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 1800 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Participants will be randomized to BCG:placebo in a 1:1 ratio.
• Masking: Double (Participant, Investigator)
• Masking Description: Randomization will be done centrally and computer generated with stratification per hospital in random blocks of 2, 4 and 6. The BCG vaccine will be administered by research nurses. Participants and investigators will be blinded. The research nurse that administers the BCG vaccine or placebo will not be blinded. This research nurse will not be involved in the collection of outcome data.
• Primary Purpose: Prevention
• Official Title: Bacillus Calmette-Guerin Vaccination as Defense Against SARS-CoV-2: A Randomized Controlled Trial to Protect Health Care Workers by Enhanced Trained Immune Responses
• Actual Study Start Date: April 20, 2020
• Estimated Primary Completion Date: May 2023
• Estimated Study Completion Date: May 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: BCG Group; FDA-approved BCG Tice strain, procured from Merck, will be used. The vaccine will be reconstituted according to the package insert. In brief, a vial containing ~1x10^8 CFU of lyophilized BCG will be reconstituted in 50 mL of saline. A single dose will consist of 0.1 mL (~2x10^5 CFU) will be administered by slow intradermal injection using a 25 gauge/ 0.5 mm syringe in the deltoid area.	Biological: BCG Vaccine; BCG vaccine will be administered by research nurses. Participants and investigators will be blinded.
Placebo Comparator: Placebo Group; A single dose will consist of 0.1 mL saline	Biological: Placebo Vaccine; Placebo vaccine will be administered by research nurses. Participants and investigators will be blinded.

Outcome Measures

Primary Outcome Measures :

1. Incidence of COVID 19 Infection [ Time Frame: 6 months ]
   The primary outcome measure is the development of COVID19 infection. We will use the Cox proportional-hazards model to calculate hazard ratios for the development of Covid-19. This will be reported as the proportion of individuals receiving the intervention who are PCR-positive or seroconvert. defined as number of new cases during the 6 month time period

Secondary Outcome Measures :

1. Disease Severity [ Time Frame: up to 6 months ]
   The secondary outcome measure is disease severity calculated using the Covid Severity Scale Scoring of 0 -10. A score of 10 is worse and a score of 0 is best. Disease severity score will be based on the level of care required for individuals who test positive for COVID19 as follows: non-hospital-based 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 criteria for severity include severe pneumonia, respiratory failure, acute respiratory distress syndrome, sepsis and septic shock.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Adult (≥18 years)
• Male or female
• Hospital personnel taking care for patients with known or suspected SARS-CoV-2 infection and providing, on average, at least 25 hours per week of direct patient care

Exclusion Criteria:

• Known allergy to (components of) the BCG vaccine or serious adverse events to prior BCG administration
• Known active or latent Mycobacterium tuberculosis or with another mycobacterial species. A history with- or a suspicion of M. tuberculosis infection.
• Fever (>38 C) within the past 24 hours
• Age > 75 years
• Pregnancy or planning pregnancy within 30 days of study enrollment
• Breastfeeding
• Suspicion of active viral or bacterial infection
• Any Immunocompromised subjects. This exclusion category comprises: a) subjects with known infection by the human immunodeficiency virus (HIV-1); b) subjects with known neutropenic with less than 1500 neutrophils/mm3; c) subjects with solid organ transplantation; d) subjects with bone marrow transplantation; e) subjects under chemotherapy; f) subjects with primary immunodeficiency; g) known severe lymphopenia with less than 400 lymphocytes/mm3; h) treatment with any anti-cytokine therapies. i) treatment with oral or intravenous steroids defined as daily doses of 10mg prednisone or equivalent for longer than 3 months
• Living with someone who is immunosuppressed or taking immunosuppressive drugs
• Previous documented infection with COVID19
• Active solid or non-solid malignancy or lymphoma within the prior two years
• Direct involvement in the design or the execution of the study
• Expected absence from work of ≥4 of the following 12 weeks due to any reason (holidays, maternity leave, retirement, planned surgery etc)
• Not in possession of a smartphone
• Inability to keep the vaccine site covered in the case of a draining pustule.

Contacts and Locations

Locations

United States, California

Cedars-Sinai Medical Center

Los Angeles, California, United States, 90048

United States, Texas

Texas A&M Family Care Clinic

Bryan, Texas, United States, 77802

Baylor College of Medicine

Houston, Texas, United States, 77030

Baylor St. Luke's Medical Center

Houston, Texas, United States, 77030

Harris Health System - Ben Taub Hospital

Houston, Texas, United States, 77030

MD Anderson Cancer Center

Houston, Texas, United States, 77030

Sponsors and Collaborators

Texas A&M University

Baylor College of Medicine

M.D. Anderson Cancer Center

Cedars-Sinai Medical Center

Harvard University

Investigators

• Principal Investigator: Jeffrey D Cirillo, PhD; Texas A&M University
• Principal Investigator: Andrew DiNardo, MD; Baylor College of Medicine
• Principal Investigator: Ashish M Kamat, MD; M.D. Anderson Cancer Center
• Principal Investigator: Moshe Arditi, MD; Cedars-Sinai Medical Center

More Information

Publications:

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• Responsible Party: Texas A&M University
• ClinicalTrials.gov Identifier: NCT04348370
• Other Study ID Numbers: 2020-0432F
• First Posted: April 16, 2020
• Last Update Posted: October 19, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: There is not a plan to make IPD available.

• 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.: No

Keywords provided by Texas A&M University:

BACILLUS CALMETTE-GUÉRIN VACCINATION; BCG Vaccine; Coronavirus; SARS-CoV-2; COVID19; COVID

Additional relevant MeSH terms:

Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Vaccines; BCG Vaccine; Immunologic Factors; Physiological Effects of Drugs; Adjuvants, Immunologic