BCG Against Covid-19 for Prevention and Amelioration of Severity Trial (BAC to the PAST)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the efficacy of Bacille Calmette-Guérin (BCG) vaccination compared to placebo in reducing severe Covid-19 disease among elderly residents of skilled nursing facilities. The investigators hypothesize that BCG vaccination can reduce severity of Covid-19 disease. Patients who are residents of participating long-term care facilities (LTCFs), with the ability to understand and cooperate with study procedures, who agree to participate in the study will be randomly assigned to receive BCG vaccination or a placebo. Participants will be followed for up to twelve months to assess severity of Covid-19 outcomes.

Detailed Description
-----------------
This is a Phase III, double-blind, randomized placebo-controlled trial comparing efficacy of BCG vaccination to that of placebo in reducing severity of Covid-19. Participants will need to meet eligibility criteria in order to be included in the study. Those selected, will be asked to provide a blood or saliva sample for Covid-19 serological test and an Interferon gamma release assay (IGRA) test for tuberculosis infection, only if IGRA or tuberculin skin test (TST) result is not available from the previous year. Participants will be randomized in a 1:1 allocation to receive intradermal administration of BCG vaccination or placebo at baseline. During follow-up, the study team will extract participants information from nursing home records regarding Covid-19-like symptoms, diagnosis, outcomes, as well as any adverse side effects of BCG vaccination. At 6 and 12 months of follow up, an additional blood or saliva sample will be collected to perform a Covid-19 serological test. The investigators will screen 2,500 individuals to enroll 2,100 participants, resulting in 1,050 receiving BCG vaccine and 1,050 receiving placebo. The proposed enrollment sample size is designed to provide 80% power to detect 60% vaccine efficacy (a relative risk of 0.4 among the vaccinated) with 0.05 type-1 error in a two-tailed test, assuming a Covid-19 attack rate of 10% in elderly NH and 38.5% severe Covid-19 among the infected patients, and a design effect = 1.2, and 15% lost during the 6-month follow-up. The number of individuals screened assumes about 20% will not be eligible/agree to be enrolled. Note that the 60% vaccine efficacy was based on the observed three-fold decline in respiratory infections in the adolescent cohort. Objective: To assess the efficacy of BCG vaccination compared to placebo in reducing severe Covid-19 disease among elderly residents of skilled nursing facilities. Primary Endpoint 1: Cases of Covid-19 disease classified as severe. Severe COVID-19 disease will be defined as: COVID-19 disease with hospitalization, death, or non-hospitalized severe disease where non-hospitalized severe disease is defined as a change in status including administration of new supplemental oxygen or decline in oxygen saturation of 10%; change from ambulant to non-ambulant status of 3+ days; new change in mental status as documented in the electronic health record The investigators will use the Cox proportional-hazards model to calculate hazard ratios for the development of severe Covid-19 between the BCG and placebo arms. If BCG vaccine is shown to be effective in this age group, it will be of major benefit to both study participants and other elderly individuals at risk for infection and disease from Covid-19. With no other vaccine alternative currently available, an efficacy of even 50% could reduce the death rate among infected patients accordingly. BCG has been reported to have a variety of other possible benefits including reduction in the risk of TB disease, Alzheimer's Disease and reduction in other respiratory infection. Because these benefits have not been proven in clinical trials, they will not be presented to potential participants.

Official Title
-----------------
Bacillus Calmette-Guerin Against Covid-19 for Prevention and Amelioration of Severity Trial

Conditions
-----------------
Covid19

Intervention / Treatment
-----------------
* Drug: BCG Vaccine
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion: Residents of a participating LTCF 70 years or older Ability to understand and cooperate with study procedures including dressing care. Nursing home staff or the research team will ensure participants are correctly doing dressing care. Exclusion: Previous or current SARS-CoV2 infection/Covid-19 disease defined by documentation of disease in clinical chart or positive PCR test. Previous or known active TB disease Does not have an established proxy or guardian, but has cognitive impairment that would prohibit the participant from fully understanding the extent of study requirements and risks, or prohibit their ability to provide informed consent. Obesity (Body Mass Index [BMI] > 35) Fever (>38 C) within the past 24 hours Current or historic serious underlying medical conditions: HIV+ History of organ or bone marrow transplantation History of major immunodeficiency disorder Active solid or hematologic malignancy diagnosed within the past two years Presence of significant neurologic disease, eg. Alzheimer's disease Receipt of any of the following drugs: Currently taking immunosuppressive or immunomodulatory drugs (inhalers and/or prednisone are acceptable to take) The Prednisone doses equivalent > 2 mg/kg or > 20 mg per day of prednisone administered for >/= 2 weeks are immunosuppressive and should be avoided with live vaccines. Expect to receive chemotherapy in the coming six months, receipt of chemotherapy in the past six months or undergoing chemotherapy Currently on any anti-cytokine therapy Taking metformin treatment Suspicion of active viral or bacterial infection Plan to leave the nursing home within the next 6 months Taking part in another intervention-based trial for Covid-19 Allergy to any component of the BCG vaccine or an anaphylactic or allergic reaction to a previous dose of BCG vaccination

Ages Eligible for Study
-----------------
Minimum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized in a 1:1 allocation to receive intradermal administration of BCG vaccination or placebo.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BCG Vaccine<br>Participants randomized to the BCG arm will receive BCG vaccine. The vaccination site is about halfway down the outer aspect of the upper arm. | Drug: BCG Vaccine<br>* .1 mL of reconstituted BCG vaccine given intradermally at baseline.<br>|
| Placebo Comparator: Placebo Arm<br>Placebo will be administered in an intradermal route in the same location as the BCG vaccines: upper arm. | Other: Placebo<br>* .1 nL of diluent (saline) given intradermally at baseline<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the efficacy of BCG vaccination compared to placebo in reducing severe Covid-19 disease among elderly residents of skilled nursing facilities. | Number of people diagnosed with severe Covid-19 disease as documented in the electronic heath record; severe Covid-19 disease is defined as any instance of death, hospitalization, or non-hospitalization but requiring new administration of supplemental oxygen or having a decline in oxygen saturation of 10%, change from ambulant to non-ambulant for 3 or more days, or any new change in mental health status. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the efficacy of BCG vaccination compared to placebo in reducing the following among elderly residents of skilled nursing facilities (by number of cases) | Number of cases of any COVID-19 disease, defined as a positive SARS-Cov-2 test (per PCR or serology), plus fever (as documented in EHR) or at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (as documented in EHR.) Number of cases of asymptomatic SARS-CoV-2 infection, defined as evidence of SARS-CoV-2 infection (by PCR or seroconversion), absence of associated respiratory illness (as documented in EHR), and no evidence of exposure prior to randomization (baseline serology will be negative). Number of cases of critical care admissions with SARS-CoV-2, defined as the number of admissions to critical care associated with a positive SARS-CoV-2 test. Number of cases of critical care admission duration with SARS-CoV-2, defined as the number of days admitted to critical care (using medical/hospital records) associated with a positive SARS-CoV-2 test. | 12 months | 
| To assess the efficacy of BCG vaccination compared to placebo in reducing the following among elderly residents of skilled nursing facilities (by number of cases), continued | 5. Number of cases of critical care admissions, defined as the number of admissions to critical care. 6. Number of cases of mechanical ventilation with SARS-CoV-2, defined as the number of participants needing mechanical ventilation (as documented by EHR) and associated with a positive SARS-CoV-2 test. 7. Number of cases of mechanical ventilation, defined as the number of participants needing mechanical ventilation. 8. Number of cases of All-Cause Mortality, defined as death reported by the long-term care facility. 9. Number of cases of any fever or respiratory illness, defined as fever (as documented in EHR), or at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (as documented in EHR). | 12 months | 
| To assess the efficacy of BCG vaccination compared to placebo in reducing the following among elderly residents of skilled nursing facilities (by number of episodes) | Number of episodes of fever or respiratory illness, defined as fever (as documented in EHR), or at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (as documented in EHR). Number of episodes of any COVID-19 disease, defined as a positive SARS-Cov-2 test (per PCR or serology), plus fever (as documented in EHR) or at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (as documented in EHR.) Number of episodes of local and systemic adverse events to BCG vaccination measured over the 3 months following randomization (type and severity of local and systemic adverse events will be collected and graded using toxicity grading scale). | 12 months | 
| To assess the efficacy of BCG vaccination compared to placebo in reducing the following among elderly residents of skilled nursing facilities (by number of days) | Number of days of symptom duration of fever or respiratory illness, defined as number of days with symptoms in any episode of illness that meets the case definition for fever or respiratory illness, defined as fever (as documented in EHR), or at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (as documented in EHR). Number of days of COVID-19 symptom duration, defined as the number of days with symptoms in any episode of illness that meets the case definition for any COVID-19 disease. | 12 months |