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COVID-19Phase 4ACTIVATEIINCT04414267

Bacillus Calmette-guérin Vaccination to Prevent COVID-19

A Phase 4 study testing BCG vaccine in people with COVID-19 and Virus Diseases, run by Hellenic Institute for the Study of Sepsis at 15 sites in Greece.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 50 years and olderHealthy volunteers can take part
Conditions the study is for
COVID-19, Virus Diseases, Corona Virus Infection
What is being tested?
BCG vaccine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
301 participants
Where
15 sitesGreece
Study dates
26 May 2020to 7 May 2021
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 50 years and older
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • Written informed consent
  • Male or female
  • 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.
  • History of at least one of the following:
  • coronary heart disease;
  • chronic obstructive pulmonary disease;
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  • Charlson's comorbidity index (CCI) more than 3
  • Negative serum testing for immunoglobulin G and M against SARS-CoV-2
  • Skin tuberculin test diameter less than 10mm

Who cannot join

  • 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
Show all 12Show fewer
  • 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

Trial locations and contacts

15 sites in 1 country.

15 sites in 1 country

Greece15 sites

  • 2nd Department of Internal Medicine, University General Hospital of Alexandroupolis

    Alexandroupoli, 68100

  • Department of Therapeutics, Alexandra General Hospital

    Athens, 115 28

  • 1st Department of Internal Medicine, General Hospital of Athens G. GENNIMATAS

    Athens, 11527

  • 2nd University Department of Internal Medicine, IPPOKRATEION General Hospital of Athens

    Athens, 11527

  • 3rd University Department of Internal Medicine, General Hospital of Chest Diseases of Athens I SOTIRIA

    Athens, 11527

  • 4th Department of Internal Medicine, "Attikon" University Hospital, National and Kapodistrian University of Athens, Medical School

    Athens, 12462

  • Department of Pulmonary Medicine- General Hospital of Kerkyra

    Corfu, 49100

  • General Hospital of Korinthos

    Corinth, 20100

  • 1st Department of Internal Medicine, General University Hospital of Ioannina

    Ioannina, 45500

  • Department of Internal Medicine, General Hospital of Karditsa

    Karditsa, 43100

  • General Hospital of Argolida - Nafplion Unit

    Nafplion, Argos, 21100

  • Department of Internal Medicine, Patras University Hospital

    Pátrai

  • General Hospital of Ptolemaida MPODOSAKEIO

    Ptolemaida, 50200

  • 1st Department of Internal Medicine, AHEPA University General Hospital of Thessaloniki

    Thessaloniki, 54621

  • General Hospital of Imathia - Veria Unit

    Véria, 59100

Other trials in Greece

About this study

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

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

Read the 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.

Being tested
BCG vaccine, Placebo
Keywords
COVID-19, SARS-CoV-2, Vaccination, Bacillus Calmette-Guérin vaccination
Medical subject headings
COVID-19, Virus Diseases, Coronavirus Infections, Coronary Disease, Pulmonary Disease, Chronic Obstructive

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BCG vaccineBiological

    Also called BCG Vaccine (Freeze Dried)

    Patients susceptible to SARS-CoV-2 infection will be vaccinated with one intradermal injection of 0.1ml of BCG vaccine

  • PlaceboBiological

    Also called Saline

    Patients susceptible to SARS-CoV-2 infection will be vaccinated with one intradermal injection of 0.1ml of sodium chloride 0.9%

Study groups in NCT04414267
Study groupRoleWhat they receive
BCG vaccineExperimentalOne intradermal injection of 0.1ml of BCG (BCG vaccine Moscow strain 361-1; Serum Institute of India Pvt. Ltd)
Receives: Biological: BCG vaccine
PlaceboPlacebo comparatorOne intradermal injection of 0.1ml of sodium chloride 0.9%
Receives: Biological: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    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

    Measured: Visit 3 (90 +/- 5 days)

Secondary outcomes (15)

  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

    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

    Measured: Visit 4 (135 +/- 5 days)

  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

    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

    Measured: Visit 5 (180 +/- 5 days)

  3. Prevalence of IgG/IgM against SARS-CoV-2

    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

    Measured: Screening Visit and Visit 3 (90 +/- 5 days)

  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.

    Itemized analysis of each of the components of the respiratory questionnaire on each study visit

    Measured: Visit 2 (45 +/- 5 days), Visit 3 (90 +/- 5 days), Visit 4 (135 +/- 5 days), Visit 5 (180 +/- 5 days)

  5. The impact of new cardiovascular events between the two study groups

    The impact of new cardiovascular events between the two study groups (placebo and BCG) will be analyzed, though the collection of any cardiovascular events occured to the enrolled patients.

    Measured: Visit 2 (45 +/- 5 days), Visit 3 (90 +/- 5 days), Visit 4 (135 +/- 5 days), Visit 5 (180 +/- 5 days)

  6. Differences in repeated measurements of angiometric parameters (arterial hardness) between the two sub-study groups in Visit 3

    Differences in repeated measurements of arterial stiffness in visit 3 between the two sub-study groups (placebo or BCG) will be analyzed through the speed of the pulse wave velocity. Pulse wave velocity is measured in m/sec.

    Measured: Visit 1 (Day 0), Visit 3 (90 +/- 5 days)

  7. Differences in repeated measurements of angiometric parameters (central arterial pressures and reflected waves) between the two sub-study groups in Visit 3

    Differences in repeated measurements of central arterial pressures and reflected waves in visit 3 between the two sub-study groups (placebo or BCG) will be measured non-invasively by pulse wave analysis. Central arterial pressure is measured in mmHg.

    Measured: Visit 1 (Day 0), Visit 3 (90 +/- 5 days)

  8. Differences in repeated measurements of angiometric parameters (endothelial function) between the two sub-study groups in Visit 3

    Differences in repeated measurements of endothelial function in visit 3 between the two sub-study groups (placebo or BCG) will be measured by ultrasound measurement of endothelium-dependent flow-mediated dilatation and by nitrate-mediated dialatation. Endothelial function will be assessed by Flow Mediated Dilatation (FMD). Endothelium-dependent: diameter of the artery prior and after temporary ischemia in is measured in mm, nitrate-mediated: diameter of the artery prior and after nitrate administration is measured in mm

    Measured: Visit 1 (Day 0), Visit 3 (90 +/- 5 days)

  9. Differences in repeated measurements of angiometric parameters (thickness of the medial carotid sheath) between the two sub-study groups in Visit 3

    Differences in repeated measurements of thickness of the medial carotid sheath in visit 3 between the two sub-study groups (placebo or BCG) will be measured by B-mode ultrasound examination. Intima-Media Thickness is measured in mm

    Measured: Visit 1 (Day 0), Visit 3 (90 +/- 5 days)

  10. Differences in repeated measurements of angiometric parameters (arterial hardness) between the two sub-study groups in Visit 5

    Differences in repeated measurements of arterial stiffness in visit 5 between the two sub-study groups (placebo or BCG) will be analyzed through the speed of the pulse wave velocity. Pulse wave velocity is measured in m/sec.

    Measured: Visit 1 (Day 0), Visit 3 (90 +/- 5 days), Visit 5 (180 +/- 5 days)

  11. Differences in repeated measurements of angiometric parameters (central arterial pressures and reflected waves) between the two sub-study groups in Visit 5

    Differences in repeated measurements of central arterial pressures and reflected waves in visit 5 between the two sub-study groups (placebo or BCG) will be measured non-invasively by pulse wave analysis. Central arterial pressure is measured in mmHg.

    Measured: Visit 1 (Day 0), Visit 3 (90 +/- 5 days), Visit 5 (180 +/- 5 days)

  12. Differences in repeated measurements of angiometric parameters (thickness of the medial carotid sheath) between the two sub-study groups in Visit 5

    Differences in repeated measurements of thickness of the medial carotid sheath in visit 5 between the two sub-study groups (placebo or BCG) will be measured by B-mode ultrasound examination. Intima-Media Thickness is measured in mm

    Measured: Visit 1 (Day 0), Visit 3 (90 +/- 5 days), Visit 5 (180 +/- 5 days)

  13. Differences in repeated measurements of angiometric parameters (endothelial function) between the two sub-study groups in Visit 5

    Differences in repeated measurements of endothelial function in visit 5 between the two sub-study groups (placebo or BCG) will be measured by ultrasound measurement of endothelium-dependent flow-mediated dilatation and by nitrate-mediated dialatation. Endothelial function will be assessed by Flow Mediated Dilatation (FMD). Endothelium-dependent: diameter of the artery prior and after temporary ischemia in is measured in mm, nitrate-mediated: diameter of the artery prior and after nitrate administration is measured in mm

    Measured: Visit 1 (Day 0), Visit 3 (90 +/- 5 days), Visit 5 (180 +/- 5 days)

  14. Differences in cardiac ultrasound at visit 5 between the two sub-study groups

    Differences in cardiac ultrasound at visit 5 between the two sub-study groups (placebo or BCG) will be assessed using standard measurements from 2-D and Doppler echocardiography.

    Measured: Visit 1 (Day 0), Visit 3 (90 +/- 5 days), Visit 5 (180 +/- 5 days)

  15. Changes in the release of cytokines from blood mononuclear cells at visit 3 between the two sub-study groups

    Changes in the release of cytokines from blood mononuclear cells at visit 3 between the two sub-study groups (placebo or BCG) will be analyzed

    Measured: Visit 1 (Day 0), Visit 3 (90 +/- 5 days)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 Jun 2020
  2. Study start26 May 2020
  3. Primary completion28 Apr 2021
  4. Study completion7 May 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Model description
Patients vaccinated with placebo or BCG
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
301 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04414267
Sponsor's protocol ID
Activate II
Other IDs
2020-002448-21
Acronym
ACTIVATEII
Status last verified
May 2021
First submitted
1 Jun 2020
Last updated
11 May 2021
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing BCG vaccine in people with COVID-19 and Virus Diseases, run by Hellenic Institute for the Study of Sepsis at 15 sites in Greece.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 11 May 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 15 sites in Greece. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome 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. (time frame: Visit 3 (90 +/- 5 days)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04414267.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 May 2021.

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