Bacillus Calmette-Guerin Vaccination as Defense Against SARS-CoV-2: A Randomized Controlled Trial to Protect Health Care Workers by Enhanced Trained Immune Responses

INTRODUCTION

  • Org Study ID: 2020-0432F
  • Secondary ID: N/A
  • NTC ID: NCT04348370
  • Sponsor: Texas A&M University

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.

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.


  • Overall Status
    Recruiting
  • Start Date
    April 20, 2020
  • Phase
    Phase 4
  • Study Type
    Interventional

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Incidence of COVID 19 Infection

Primary Outcome 1 - Timeframe: 6 months

CONDITION

  • Coronavirus
  • Coronavirus Infection
  • Coronavirus as the Cause of Diseases Classified Elsewhere

ELIGIBILITY


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.

Gender: All

Minimum Age: 75 Years

Maximum Age: 18 Years

Healthy Volunteers: Accepts Healthy Volunteers

OFFICIAL INFORMATION

Name: Jeffrey D Cirillo, PhD

Role: Principal Investigator

Affiliation: Texas A&M University

Overall Contact

Name: Jeffrey D Cirillo, PhD

Phone: 979 436-0343

Email: jdcirillo@tamu.edu

LOCATION

Facility Status Contact
Facility: Cedars-Sinai Medical Center
Los Angeles, California 90048
United States
Status: Recruiting Contact:
Pablo Avalos, MD
310-248-8571
Pablo.Avalos@cshs.org
Facility: Texas A&M Family Care Clinic
Bryan, Texas 77802
United States
Status: Recruiting Contact:
Gabriel A Neal, MD
979-436-0431
gneal@tamu.edu
Facility: Baylor College of Medicine
Houston, Texas 77030
United States
Status: Recruiting Contact:
Andrew DiNardo, MD
832-822-1038
Andrew.Dinardo@Bcm.Edu
Facility: Baylor St. Luke's Medical Center
Houston, Texas 77030
United States
Status: Recruiting Contact:
Seth Lerner, MD
713-798-5553
slerner@bcm.edu
Facility: Harris Health System - Ben Taub Hospital
Houston, Texas 77030
United States
Status: Recruiting Contact:
Andrew DiNardo, MD
832-822-1038
Andrew.Dinardo@Bcm.Edu
Facility: MD Anderson Cancer Center
Houston, Texas 77030
United States
Status: Recruiting Contact:
Marisa Lozano
713-794-4397
mllozano@mdanderson.org