Clinical trial NCT04461379: Prevention, Efficacy and Safety of BCG Vaccine in COVID-19 Among Healthcare Workers
Official title: Prevention, Efficacy and Safety of BCG Vaccine in COVID-19- Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: BCG
COVID-19
SARS-CoV2
Corona Virus Infection
Keywords: Healthcare workers
Lead sponsor: Hospital Universitario Dr. Jose E. Gonzalez
Sponsor class: OTHER
First posted: 2020-07-08
Enrollment: 908
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A randomized double-blinded clinical trial, using computer software, participants will be allocated between two groups:

Intervention: BCG vaccine intradermally 0.1 ml, equivalent to 0.075 mg of attenuated Mycobacterium bovis. (Tokio 172 strain). The application technique is based on the National Vaccination Manual version 2017.

Comparator: Placebo, intradermally 0.1 ml of NaCl 0.9%
Primary purpose: PREVENTION

Brief summary: In Mexico the total number of confirmed cases of COVID-19 is 232, 000 and 28,510 deaths. Health workers are at high risk of COVID-19 infection. Their absence from work dramatically limits the ability to contain the disease. There is currently no vaccine to prevent the disease. Since the introduction to the vaccination schedule of the Bacillus Calmette-Guerin (BCG) live attenuated vaccine directed towards tuberculosis prevention, a decrease in infant mortality has been reported, not related only to tuberculosis. BCG vaccine has been hypothesized to have a non-specific role towards other unrelated pathogens such as viruses that cause airway disease, with reduced morbidity and mortality. In murine as well as in human models it has been shown to decrease the incidence of acute respiratory influenza infections. Likewise, in countries with a high endemicity for tuberculosis, the BCG vaccine reduces the incidence of respiratory infections by up to 80% . In healthy subjects, the BCG vaccine increases the production of proinflammatory cytokines in monocytes. Likewise, it increases the epigenetic response, causing an increase in the transcription of genes important in the antimicrobial response, as well as an improvement in cellular function. This is the first national clinical trial to evaluate prospectively the effect that the BCG vaccine offers towards the prevention and reduction of severity in cases of COVID-19.

Detailed description: The study design is a randomized, double-blinded, placebo-controlled clinical trial.

Age stratified randomization (\<45 years and\> 45 years) was performed using permuted blocks with allocation concealment.

The sample size is 908 patients. 454 patients in each stratum (227 with placebo and 227 with BCG vaccine).

Eligible participants will be healthcare professionals over 18 years of age who are in contact with patients with COVID-19, with negative IgG and IgM antibodies results for SARS-CoV-2 prior to their inclusion and sign the informed consent. After signing the informed consent, the participants will be randomized 1:1 to the intervention group (BCG vaccine) or control (placebo), a medical history will be performed, and a blood plasma sample will be obtained to determine specific antibodies against SARS-CoV-2.

The patients will be followed up for 6 months after the application of the vaccine, they will be contacted by phone every two weeks in order to identify the adverse effects of the vaccine (30 days after the application) as well as to identify symptoms of COVID-19, in addition, follow-up visits will be carried out at the third and sixth months, in each of these visits a blood plasma sample will be obtained and IgG and IgM antibodies will be measured.

Statistical Analysis Type: By intention to treatment

Eligibility criteria: Inclusion Criteria:

* Health workers who are working onsite in patients' areas with COVID-19
* Age \> 18 years
* Negative specific IgG and IgM antibodies test result for SARS CoV-2 before the enrollment.
* Provide a signed and dated informed consent form

Exclusion Criteria:

* Age \<18 years
* Positive test for specific antibodies IgG and IgM antibodies result for SARS Cov-2
* Primary or secondary immunosuppression
* Use of immunosuppression drugs, use of hydroxychloroquine, cloroquine, Azithromycin, Lopinavir/ritonavir, Ivermectin or any other drug used to treat patients COVID-19 before the enrollment.
* Chemotherapy treatment
* Presence of antibodies IgA, IgM, IgG against SARS-CoV-2
* Pregnancy or breastfeeding
* Missing informed consent form
* Fever \> 38° in the previous 24 hours
* Any BCG vaccine contraindication
* History of previous allergy to the components of the vaccine
* Already part of any other trial
* Previous or active tuberculosis (TB) disease
* Another vaccine administrated 4 months before the start of the trial.
* Any underlying history of malignancy or lymphoma.
* Actual treatment with steroids
* Absence of more than 1 month from the hospital, from the study period.

Primary outcomes:
measure: Demonstrate COVID- 19 disease incidence among Health care workers:
timeFrame: During the 6 months study period
measure: Demonstrate cumulative incidence of hospitalization for COVID-19 among Health care workers:
timeFrame: During the 6 months study period
measure: Demonstrate the Incidence of specific Antibodies against SARS-CoV-2 at 3 and 6 months in health care workers
timeFrame: During the 6 months study period
measure: Hospitalization of severe disease COVID-19
timeFrame: During the 6 months study period
measure: Oxygen supplementation in severe disease COVID-19
timeFrame: During the 6 months study period
measure: Need for intubation or non-invasive ventilation for the patient.
timeFrame: During the 6 months study period
measure: Critical care admission with SARS-CoV2
timeFrame: During the 6 months study period
measure: Mortality associated to progressive pulmonary disease
timeFrame: During the 6 months study period
Secondary outcomes:
measure: Evaluate the safety of the vaccine by measuring the incidence rates of local and systemic adverse effects that occur after one month its application.
timeFrame: 1 month after vaccine/placebo application
measure: Calculate the incidence of COVID-19 complications
timeFrame: During the 6 months study period
measure: Determine the mean days of hospitalization and days in intensive care unit by COIVD-19
timeFrame: During the 6 months study period
measure: Calculate the cost associated with in-hospital medical care
timeFrame: During the 6 months study period
measure: Determine the scores of the Clinical Prediction Rules associated with mortality using Sequential Organ Failure Assessment (SOFA score) at the patient's hospital admission:
timeFrame: During the 6 months study period
measure: Determine the scores of the Clinical Prediction Rules associated with mortality using Acute Physiology and Chronic Health disease Classification System (APACHE) at the patient's hospital admission:
timeFrame: During the 6 months study period
measure: Evaluate and determine the alteration profile in laboratory studies at the patient's hospital admission
timeFrame: During the 6 months study period
measure: Registration of chronic medications
timeFrame: During the 6 months study period
measure: Need for vasopressors
timeFrame: During the 6 months study period
Other outcomes:
Locations:
city: Monterrey
country: Mexico
facility: Hospital Universitario "José E. González"
state: Nuevo León
Study officials:
References: