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Bacillus Calmette-guérin Vaccination to Prevent COVID-19 (ACTIVATEII)

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ClinicalTrials.gov Identifier: NCT04414267
Recruitment Status : Recruiting
First Posted : June 4, 2020
Last Update Posted : June 17, 2020
Sponsor:
Information provided by (Responsible Party):
Hellenic Institute for the Study of Sepsis

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.

Condition or disease Intervention/treatment Phase
COVID-19 Virus Diseases Corona Virus Infection Coronary Heart Disease Chronic Obstructive Pulmonary Disease Biological: BCG vaccine Biological: Placebo Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 900 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Patients vaccinated with placebo or BCG
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
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
Actual Study Start Date : May 26, 2020
Estimated Primary Completion Date : May 25, 2021
Estimated Study Completion Date : May 25, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: BCG vaccine
One intradermal injection of 0.1ml of BCG (BCG vaccine Moscow strain 361-1; Serum Institute of India Pvt. Ltd)
Biological: BCG vaccine
Patients susceptible to SARS-CoV-2 infection will be vaccinated with one intradermal injection of 0.1ml of BCG vaccine
Other Name: BCG Vaccine (Freeze Dried)

Placebo Comparator: Placebo
One intradermal injection of 0.1ml of sodium chloride 0.9%
Biological: Placebo
Patients susceptible to SARS-CoV-2 infection will be vaccinated with one intradermal injection of 0.1ml of sodium chloride 0.9%
Other Name: Saline




Primary Outcome Measures :
  1. 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. [ Time Frame: Visit 3 (90 +/- 5 days) ]

    This is set on visit 3 (90 ± 5 days from the date of visit 1). The two groups of vaccination are compared for the primary endpoints which is composite. Patients who meet any of the following will be considered to meet the primary endpoint:

    • Positive for the respiratory questionnaire endpoint when at least one of the following combination is met either at visit 2 and/or at visit 3:

      • One situation definitively related to COVID-19
      • All four questions of symptoms possibly related to COVID-19
      • At least two questions of symptoms possibly related to COVID-19 as well as need for admission at the emergency department of any hospital and/or need for intake of antibiotics
      • At least four questions of symptoms probably related to COVID-19 one of which is "need for admission at the emergency department of any hospital and/or need for intake of antibiotics"
    • Positive IgG or IgM antibodies against SARS-CoV-2


Secondary Outcome Measures :
  1. Positive respiratory questionnaire endpoint consisted of questions concerning the appearance of symptoms possibly, probably and/or definitively related to COVID-19 on visit 4 [ Time Frame: Visit 4 (135 +/- 5 days) ]
    The two groups of vaccination are compared for the primary endpoints which is composite (as defined at primary study endpoint) and meet a positive respiratory questionnaire endpoint on visit 4

  2. Positive respiratory questionnaire endpoint consisted of questions concerning the appearance of symptoms possibly, probably and/or definitively related to COVID-19 on visit 5 [ Time Frame: Visit 5 (180 +/- 5 days) ]
    The two groups of vaccination are compared for the primary endpoints which is composite (as defined at primary study endpoint) and meet a positive respiratory questionnaire endpoint (as defined at primary study endpoint) on visit 5

  3. Prevalence of IgG/IgM against SARS-CoV-2 [ Time Frame: Screening Visit and Visit 3 (90 +/- 5 days) ]
    Prevalence of IgG/IgM against SARS-CoV-2 will be measured among the patients who failed the eligibility procedure and the patients that were eligible and were enrolled

  4. 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. [ Time Frame: Visit 2 (45 +/- 5 days), Visit 3 (90 +/- 5 days), Visit 4 (135 +/- 5 days), Visit 5 (180 +/- 5 days) ]
    Itemized analysis of each of the components of the respiratory questionnaire on each study visit



Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04414267


Contacts
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Contact: Evangelos Giamarellos-Bourboulis, MD, PhD +302107480662 egiamarel@med.uoa.gr
Contact: Antigoni Kotsaki, MD, PhD +306946637164 antigonebut@yahoo.com

Locations
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Greece
General Hospital of Argolida - Nafplion Unit Recruiting
Náfplio, Argos, Greece, 21100
Contact: Konstantinos Katsaros, MD    +306973696777    k.katsaros@yahoo.gr   
2nd Department of Internal Medicine, University General Hospital of Alexandroupolis Recruiting
Alexandroupolis, Greece, 68100
Contact: Periklis Panagopoulos, MD, PhD    +30 2551351592    ppanago@med.duth.gr   
1st Department of Internal Medicine, General Hospital of Athens G. GENNIMATAS Recruiting
Athens, Greece, 11527
Contact: Georgios Adamis, MD    +30 2107768534    geo.adamis@gmail.com   
2nd University Department of Internal Medicine, IPPOKRATEION General Hospital of Athens Recruiting
Athens, Greece, 11527
Contact: Helen Sambatakou    +30 6977476385    helensambatakou@msn.com   
3rd University Department of Internal Medicine, General Hospital of Chest Diseases of Athens I SOTIRIA Recruiting
Athens, Greece, 11527
Contact: Garyfallia Poulakou, MD, PhD    +30 2107719975    gpoulakou@gmail.com   
4th Department of Internal Medicine, "Attikon" University Hospital, National and Kapodistrian University of Athens, Medical School Recruiting
Athens, Greece, 12462
Contact: Antonios Papadopoulos, MD, PhD    00302105831646    antpapa1@otenet.gr   
1st Department of Internal Medicine, General University Hospital of Ioannina Recruiting
Ioánnina, Greece, 45500
Contact: Charalambos Milionis, MD, PhD    +30 2651362736    hmilioni@uoi.gr   
General Hospital of Korinthos Recruiting
Kórinthos, Greece, 20100
Contact: Christos Chasikidis, MD       chasikid@otenet.gr   
Department of Internal Medicine, Patras University Hospital Recruiting
Patras, Greece
Contact: Charalambos Gogos, MD, PhD    +306944799784    cgogos@med.upatras.gr   
Contact: Karolina Akinosoglou, MD, PhD    +306977762897    akin@upatras.gr   
General Hospital of Ptolemaida MPODOSAKEIO Recruiting
Ptolemaḯda, Greece, 50200
Contact: Konstantinos Dolianitis, MD    +302463351548    kdolianitis@gmail.com   
1st Department of Internal Medicine, AHEPA University General Hospital of Thessaloniki Recruiting
Thessaloníki, Greece, 54621
Contact: Simeon Metallidis, MD, PhD    +30 2313303214    metallidissimeon@yahoo.gr   
General Hospital of Imathia - Veria Unit Recruiting
Véria, Greece, 59100
Contact: Christos Koutras, MD    +3023331351273    criskoutr@yahoo.gr   
Sponsors and Collaborators
Hellenic Institute for the Study of Sepsis
Investigators
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Principal Investigator: Antonios Papadopoulos, MD, PhD National Kapodistrian University of Athens, Medical School
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Responsible Party: Hellenic Institute for the Study of Sepsis
ClinicalTrials.gov Identifier: NCT04414267    
Other Study ID Numbers: Activate II
2020-002448-21 ( EudraCT Number )
First Posted: June 4, 2020    Key Record Dates
Last Update Posted: June 17, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hellenic Institute for the Study of Sepsis:
COVID-19
SARS-CoV-2
Vaccination
Bacillus Calmette-Guérin vaccination
Additional relevant MeSH terms:
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Infection
Coronavirus Infections
Severe Acute Respiratory Syndrome
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Heart Diseases
Coronary Disease
Virus Diseases
Lung Diseases
Respiratory Tract Diseases
Cardiovascular Diseases
Myocardial Ischemia
Vascular Diseases
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Respiratory Tract Infections
Vaccines
BCG Vaccine
Immunologic Factors
Physiological Effects of Drugs
Adjuvants, Immunologic