BCG Vaccine for Health Care Workers as Defense Against COVID 19 (BADAS)
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|ClinicalTrials.gov Identifier: NCT04348370|
Recruitment Status : Recruiting
First Posted : April 16, 2020
Last Update Posted : May 27, 2020
|First Submitted Date ICMJE||March 30, 2020|
|First Posted Date ICMJE||April 16, 2020|
|Last Update Posted Date||May 27, 2020|
|Actual Study Start Date ICMJE||April 20, 2020|
|Estimated Primary Completion Date||May 2021 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||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
|Original Primary Outcome Measures ICMJE
||incidence (measured by confirmed positive test) of SARS-CoV2 infection following BCG vaccination compared to placebo [ Time Frame: Measured daily for up to 6 months ]
defined as number of new cases during the 6 month time period
|Current Secondary Outcome Measures ICMJE
||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.
|Original Secondary Outcome Measures ICMJE
||COVID19-related disease severity (measured by ordinal severity scale) following BCG vaccination compared to placebo [ Time Frame: up to 6 months ]
The ordinal severity scale that will be used is:
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||BCG Vaccine for Health Care Workers as Defense Against COVID 19|
|Official Title ICMJE||Bacillus Calmette-Guerin Vaccination as Defense Against SARS-CoV-2: A Randomized Controlled Trial to Protect Health Care Workers by Enhanced Trained Immune Responses|
|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.|
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)
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:
Who they live with
Smoking status/tobacco 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
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
Other Covid-19 symptoms
Admitted to hospital
Treated in intensive care
Acute respiratory distress syndrome
*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 Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 4|
|Study Design ICMJE||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)
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
|Study Arms ICMJE||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Estimated Study Completion Date ICMJE||November 2021|
|Estimated Primary Completion Date||May 2021 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years to 75 Years (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||Yes|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT04348370|
|Other Study ID Numbers ICMJE||2020-0432F|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Responsible Party||Texas A&M University|
|Study Sponsor ICMJE||Texas A&M University|
|PRS Account||Texas A&M University|
|Verification Date||May 2020|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP