Official Title
Efficiency in Management of Organ Dysfunction Associated With Infection by the Novel SARS-CoV-2 Virus (COVID-19) Through a Personalized Immunotherapy Approach: the ESCAPE Clinical Trial
Brief Summary

Our aim is to conduct one trial of personalized immunotherapy in patients with SARS-CoV-2 (COVID-19) associated with organ dysfunction and with laboratory findings of macrophage activation syndrome or immune dysregulation. These patients will be selected by the use of a panel of biomarkers and laboratory findings and they will be allocated to immunotherapy treatment according to their needs.

Detailed Description

Humanity is experiencing since November 2019 a new pandemic by the novel SARS Coronavirus-19
(SARS-CoV-2). As of March 16 2020 170,191 documented case were reported worldwide of which
6,526 died1. The analysis of the clinical characteristics of these patients showed that among
those who were critically ill with acute respiratory failure the risk of death was as high as
60%2. Main clinical feature is the presence of comorbidities and age more than 60 years
whereas main laboratory findings are leukopenia and lymphopenia with hepatic dysfunction and
increase of D-dimers3,4. It is also reported that these patients suffer from intense
pro-inflammation where hyper-cytokinemia predominates5,6.

The above characteristics lead to consider two main mechanisms of pathogenesis of this
critical condition: macrophage activation syndrome (MAS) and immune dysregulation. Early and
correct understanding of the mechanism and management are of prime importance. This can be
achieved only through a therapeutic protocol where the early recognition of the immune state
can be done with the use of biomarkers and with the delivery of the precise treatment aiming
to the correction of the immune dysregulation.

Data of the Hellenic Sepsis Study Group indicate that MAS can be diagnosed with reliability
using serum ferritin7. Concentrations greater than 4,420ng/ml possess diagnostic specificity
97.3% and negative predictive value 98%. According to these data, the risk of developing MAS
is greater among patients with comorbidities like type 2 diabetes mellitus and heart failure
who are prone to hyper-production of interleukin (IL)-1β by tissue macrophages8. A recent
retrospective analysis of patients with severe sepsis and MAS showed that the administration
of anakinra decreased 28-day mortality by 30%9. Anakinra is the recombinant antagonist of
human IL-1β receptor. IL-1β over-production is the hallmark of the pathogenesis of MAS.
Results of a phase III study in 906 patients showed that anakinra was a very safe drug: there
was neither excess mortality nor increased susceptibility to secondary infections9. Since
November 2017 the randomized clinical trial entitled "A trial of validation and restoration
of immune dysfunction in severe infections and sepsis, PROVIDE" (EudraCT number:
2017-002171-26, approval 78/17 by the National Ethics Committee, approval IS 75/17 by the
National Organization for Medicines, NCT03332225). In this study patients
with sepsis and laboratory diagnosis of MAS are randomized to treatment with placebo or
anakinra for seven days. Enrolment was completed in December 2019 and no drug related adverse
events have been reported.

Recent unpublished data of the Hellenic Sepsis Study Group demonstrate that patients with
immune dysregulation have profound lymphopenia associated with elevated IL-6. This is in
accordance with evidence of the H1N1 pandemic where patients with pneumonia had substantial
lymphopenia and increased Τ regulatory lymphocytes (Treg). This increase of Τreg was
prominent among patients with comorbidities like diabetes mellitus, chronic heart failure and
chronic obstructive pulmonary disease10,11. The IL-6 blocker tocilizumab is a promising
candidate for the reversal of this immune dysregulation.

ESCAPE is an address to the personalized management of life-threatening organ dysfunction by
SARS-CoV-2. More precisely, patients infected by SARS-CoV-2 associated with MAS and immune
dysregulation will be administered treatment with anakinra and tocilizumab respectively.

Virus Diseases
Macrophage Activation Syndrome
Corona Virus Infection

Drug: Anakinra

In case of diagnosis of MAS treatment with anakinra
Other Name: kineret

Drug: Tocilizumab

In case of diagnosis of immune dysregulation treatment with tocilizumab
Other Name: RoActemra

Eligibility Criteria

Inclusion Criteria:

- Age equal to or above 18 years

- Male or female gender

- In case of women, unwillingness to remain pregnant during the study period.

- Written informed consent provided by the patient or by one first-degree
relative/spouse in case of patients unable to consent

- Confirmed infection by SARS-CoV-2 virus using molecular techniques as defined by the
World Health Organization11

- Organ dysfunction defined as the presence of at least one of the following conditions:

- Total SOFA score greater than or equal to 2;

- Involvement of the lower respiratory tract

- Laboratory documentation of MAS or immune dysregulation. MAS is documented by the
findings of any serum ferritin greater than 4,420ng/ml. immune dysregulation is
documented by the combination of two findings: a) serum ferritin equal to or lower
than 4,420ng/ml; and b) less than 5,000 receptors of the membrane molecule of HLA-DR
on the cell membrane of blood CD14-monocytes or less than 30 MFI of HLA-DR on the cell
membrane of blood CD14-monocytes as counted by flow cytometry

Exclusion Criteria:

- Age below 18 years

- Denial for written informed consent

- Any stage IV malignancy

- Any do not resuscitate decision

- Active tuberculosis (TB) as defined by the co-administration of drugs for the
treatment of TB

- Infection by the human immunodeficiency virus (HIV)

- Any primary immunodeficiency

- Oral or IV intake of corticosteroids at a daily dose equal or greater than 0.4 mg
prednisone or greater the last 15 days.

- Any anti-cytokine biological treatment the last one month

- Medical history of systemic lupus erythematosus

- Medical history of multiple sclerosis or any other demyelinating disorder.

- Pregnancy or lactation. Women of child-bearing potential will be screened by a urine
pregnancy test before inclusion in the study

Eligibility Gender
Eligibility Age
Minimum: 18 Years ~ Maximum: N/A

2nd Department of Critical Care Medicine, ATTIKON University Hospital
Athens, Haidari, Greece

Intensive Care Unit, Ioannina University Hospital
Ioánnina, Ioannina, Greece

Department of Internal Medicine, Patras University Hospital
Patras, Rion, Greece

Department of Internal Medicine, I PAMMAKARISTOS Hospital
Athens, Greece

Intensive Care Unit, General Hospital of Athens KORGIALENIO-BENAKIO E.E.S.
Athens, Greece

1st Department of Pulmonary Medicine and Intensive Care Unit
Athens, Greece

Intensive Care Unit, General Hospital of Athens IPPOKRATEIO
Athens, Greece

4th Department of Internal Medicine, Attikon University Hospital
Athens, Greece

Intensive Care Unit, General Hospital ASKLEPIEIO Voulas
Athens, Greece

Intensive Care Unit, "Latsio", Thriasio Elefsis General Hospital
Elefsína, Greece

Intensive Care Unit, "Koutlimbaneio & Triantafylleio" Larissa General Hospital
Larissa, Greece

Department of Internal Medicine, Larissa University Hospital
Larissa, Greece

Intensive Care Unit, AGIOS DIMITRIOS General Hospital of Thessaloniki
Thessaloniki, Greece

Intensive Care Unit, G. GENNIMATAS General Hospital of Thessaloniki
Thessaloniki, Greece

Intensive Care Unit, Theageneio Oncological Hospital of Thessaloniki
Thessaloniki, Greece

Intensive Care Unit, General Hospital of Thessaloniki IPPOKRATEIO
Thessaloniki, Greece

Department of Anesthesiology and Intensive Care Medicine, University General Hospital of Thessaloniki AHEPA
Thessaloniki, Greece

Apostolos Armaganidis, MD, PhD, Principal Investigator
National Kapodistrian University of Athens, Medical School

Hellenic Institute for the Study of Sepsis
NCT Number
MeSH Terms
Virus Diseases
Coronavirus Infections
Macrophage Activation Syndrome
Interleukin 1 Receptor Antagonist Protein