Clinical trial NCT04414267: Bacillus Calmette-guérin Vaccination to Prevent COVID-19
Official title: A Randomized Clinical Trial for Enhanced Trained Immune Responses Through Bacillus Calmette-Guérin Vaccination to Prevent Infections by COVID-19: The ACTIVATE II Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: COVID-19
Virus Diseases
Corona Virus Infection
Coronary Heart Disease
Chronic Obstructive Pulmonary Disease
Keywords: COVID-19
SARS-CoV-2
Vaccination
Bacillus Calmette-Guérin vaccination
Lead sponsor: Hellenic Institute for the Study of Sepsis
Sponsor class: OTHER
First posted: 2020-06-04
Enrollment: 301
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients vaccinated with placebo or BCG
Primary purpose: PREVENTION

Brief summary: Based on findings of the interim analysis of the ACTIVATE study showing 53% decrease of the incidence of all new infections with BCG vaccination, a new trial is designed aiming to validate if BCG can protect against COVID-19 (Corona Virus Disease-19).The aim of the study is to demonstrate in a double-blind, placebo-controlled approach if vaccination of participants susceptible to COVID-19 with BCG vaccine may modulate their disease susceptibility for COVID-19. This will be validated using both clinical and immunological criteria. At the same time, a sub-study will be conducted and the mechanism of benefit from BCG vaccination by assessing its effect on vascular endothelial function and mononuclear blood cells will be studied

Detailed description: Infection by the novel SARS-CoV-2 virus (also known as COVID-19) has tremendous social impact. Most of Western societies are at major or part lock-down whatever brings unpredictable financial and societal consequences. The urgent need for the reversal of this situation can only be met through the generation of an immune defence shield to protect the society from COVID-19. Many efforts for the development of a vaccine are under way without any specific outcome so for.

The stimulation of trained immune responses seems the only alternative to bridge the gap from the turn-on of the society until the entrance of a specific vaccine in the market. Trained immunity stands for the non-specific raise of defense shield for severe infections coming once tissue macrophages recognize a universal pathogen. The concept was successfully tested in healthy volunteers that were vaccinated with placebo or BCG (Bacillus Calmette-Guérin) vaccine. These volunteers were injected 14 days latter a tri-valent influenza A vaccine. Volunteers previously vaccinated by BCG developed significantly greater titers against hemagglutinin A of the influenza A virus whereas their circulating monocytes were more potent for the production of interferon-gamma.

It is proposed that this BCG vaccination triggering trained immune responses may play a role of protection against the COVID-19 pandemic. A solid background on this rationale came recently from the interim analysis of the ACTIVATE trial. ACTIVATE (A randomized Clinical trial for enhanced Trained Immune responses through Bacillus Calmette-Guérin VAccination to prevenT infections of the Elderly) was a prospective randomized open-label controlled trial conducted among patients hospitalized at the 4th Department of Internal Medicine of ATTIKON University General Hospital in Greece. The protocol was approved by the National Ethics Committee of Greece and the National Organization for Medicine of Greece (EudraCT number, 2017-000596-87; ClinicalTrials.gov NCT03296423). The trial is conducted and funded by the Hellenic Institute for the Study of Sepsis. In this trial hospitalized elderly patients were vaccinated on the day of hospital discharge with single doses of placebo or BCG. Every patient is under follow-up for 12 months. The last visit of the last patient is scheduled for August 2020. An interim analysis took place on April 29th 2020 by an independent committee of experts. The full interim analysis focused on the study primary endpoint that was the comparative time to a new infection between the two groups of treatment. Infections counting against this primary endpoint were respiratory or viral infections necessitating medical treatment, community-acquired pneumonias, hospital-acquired pneumonias, intraabdominal infections, urinary tract infections, soft tissue infections and bloodstream infections. Analysis revealed 53% decrease of the incidence of new infections in the BCG group compared to the placebo group. This decrease reached 80% for all respiratory tract infections. Multivariate analysis showed that most of benefit was for patients with coronary heart disease (CHD) and chronic obstructive pulmonary disease (COPD). This interim analysis clearly enhances the concept that BCG can be protective against COVID-19.

Eligibility criteria: Inclusion Criteria:

1. Written informed consent
2. Male or female
3. Age more than or equal to 50 years based on the precise date of birth. Female participants are allowed on the premise that they are post-menopausal.
4. History of at least one of the following:

   1. coronary heart disease;
   2. chronic obstructive pulmonary disease;
   3. Charlson's comorbidity index (CCI) more than 3
5. Negative serum testing for immunoglobulin G and M against SARS-CoV-2
6. Skin tuberculin test diameter less than 10mm

Exclusion Criteria:

* Deny to written informed consent
* Age less than 50 years
* Known infection by the Human Immunodeficiency Virus-1 (HIV-1)
* Severely immunocompromised patients. This exclusion category comprises:

  * History of congenital immunodeficiency
  * History of solid organ transplantation
  * History of bone marrow transplantation
  * Intake of chemotherapy the last two months
  * Intake of radiotherapy the last two months
  * Active hematological or solid tumor malignancy
  * History of any anti-cytokine therapies
  * History of oral or intravenous steroids defined as daily doses of 10mg prednisone or equivalent for longer than the last 3 months

Primary outcomes:
measure: Positive for the respiratory questionnaire consisted of questions concerning the appearance of symptoms possibly, probably and/or definitively related to COVID-19 on visit 3.
timeFrame: Visit 3 (90 +/- 5 days)
Secondary outcomes:
measure: Positive respiratory questionnaire endpoint consisted of questions concerning the appearance of symptoms possibly, probably and/or definitively related to COVID-19 on visit 4
timeFrame: Visit 4 (135 +/- 5 days)
measure: Positive respiratory questionnaire endpoint consisted of questions concerning the appearance of symptoms possibly, probably and/or definitively related to COVID-19 on visit 5
timeFrame: Visit 5 (180 +/- 5 days)
measure: Prevalence of IgG/IgM against SARS-CoV-2
timeFrame: Screening Visit and Visit 3 (90 +/- 5 days)
measure: Analysis of each of the components of the respiratory questionnaire consisted of questions concerning the appearance of symptoms possibly, probably and/or definitively related to COVID-19.
timeFrame: Visit 2 (45 +/- 5 days), Visit 3 (90 +/- 5 days), Visit 4 (135 +/- 5 days), Visit 5 (180 +/- 5 days)
measure: The impact of new cardiovascular events between the two study groups
timeFrame: Visit 2 (45 +/- 5 days), Visit 3 (90 +/- 5 days), Visit 4 (135 +/- 5 days), Visit 5 (180 +/- 5 days)
measure: Differences in repeated measurements of angiometric parameters (arterial hardness) between the two sub-study groups in Visit 3
timeFrame: Visit 1 (Day 0), Visit 3 (90 +/- 5 days)
measure: Differences in repeated measurements of angiometric parameters (central arterial pressures and reflected waves) between the two sub-study groups in Visit 3
timeFrame: Visit 1 (Day 0), Visit 3 (90 +/- 5 days)
measure: Differences in repeated measurements of angiometric parameters (endothelial function) between the two sub-study groups in Visit 3
timeFrame: Visit 1 (Day 0), Visit 3 (90 +/- 5 days)
measure: Differences in repeated measurements of angiometric parameters (thickness of the medial carotid sheath) between the two sub-study groups in Visit 3
timeFrame: Visit 1 (Day 0), Visit 3 (90 +/- 5 days)
measure: Differences in repeated measurements of angiometric parameters (arterial hardness) between the two sub-study groups in Visit 5
timeFrame: Visit 1 (Day 0), Visit 3 (90 +/- 5 days), Visit 5 (180 +/- 5 days)
measure: Differences in repeated measurements of angiometric parameters (central arterial pressures and reflected waves) between the two sub-study groups in Visit 5
timeFrame: Visit 1 (Day 0), Visit 3 (90 +/- 5 days), Visit 5 (180 +/- 5 days)
measure: Differences in repeated measurements of angiometric parameters (thickness of the medial carotid sheath) between the two sub-study groups in Visit 5
timeFrame: Visit 1 (Day 0), Visit 3 (90 +/- 5 days), Visit 5 (180 +/- 5 days)
measure: Differences in repeated measurements of angiometric parameters (endothelial function) between the two sub-study groups in Visit 5
timeFrame: Visit 1 (Day 0), Visit 3 (90 +/- 5 days), Visit 5 (180 +/- 5 days)
measure: Differences in cardiac ultrasound at visit 5 between the two sub-study groups
timeFrame: Visit 1 (Day 0), Visit 3 (90 +/- 5 days), Visit 5 (180 +/- 5 days)
measure: Changes in the release of cytokines from blood mononuclear cells at visit 3 between the two sub-study groups
timeFrame: Visit 1 (Day 0), Visit 3 (90 +/- 5 days)
Other outcomes:
Locations:
city: Náfplio
country: Greece
facility: General Hospital of Argolida - Nafplion Unit
state: Argos
city: Alexandroupolis
country: Greece
facility: 2nd Department of Internal Medicine, University General Hospital of Alexandroupolis
city: Athens
country: Greece
facility: Department of Therapeutics, Alexandra General Hospital
city: Athens
country: Greece
facility: 1st Department of Internal Medicine, General Hospital of Athens G. GENNIMATAS
city: Athens
country: Greece
facility: 2nd University Department of Internal Medicine, IPPOKRATEION General Hospital of Athens
city: Athens
country: Greece
facility: 3rd University Department of Internal Medicine, General Hospital of Chest Diseases of Athens I SOTIRIA
city: Athens
country: Greece
facility: 4th Department of Internal Medicine, "Attikon" University Hospital, National and Kapodistrian University of Athens, Medical School
city: Corfu
country: Greece
facility: Department of Pulmonary Medicine- General Hospital of Kerkyra
city: Ioánnina
country: Greece
facility: 1st Department of Internal Medicine, General University Hospital of Ioannina
city: Kardítsa
country: Greece
facility: Department of Internal Medicine, General Hospital of Karditsa
city: Kórinthos
country: Greece
facility: General Hospital of Korinthos
city: Patras
country: Greece
facility: Department of Internal Medicine, Patras University Hospital
city: Ptolemaḯda
country: Greece
facility: General Hospital of Ptolemaida MPODOSAKEIO
city: Thessaloníki
country: Greece
facility: 1st Department of Internal Medicine, AHEPA University General Hospital of Thessaloniki
city: Véria
country: Greece
facility: General Hospital of Imathia - Veria Unit
Study officials:
affiliation: National Kapodistrian University of Athens, Medical School
name: Antonios Papadopoulos, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: