The SAVE-MORE is a pivotal, confirmatory, phase III randomized clinical trial (RCT) aiming to evaluate the efficacy and safety of early start of anakinra guided by suPAR in patients with LRTI by SARS-CoV-2 in improving the clinical state of COVID-19 over 28 days as measured by the ordinal scale of the 11-point World Health Organization (WHO) clinical progression scale (CPS).
Since March 2020 when the COVID-19 pandemic started in Europe, the Hellenic Institute for the
Study of Sepsis has launched in Greece the SAVE clinical trial (suPAR-guided Anakinra
treatment for Validation of the risk and Early management of severe respiratory failure by
COVID-19) (EudraCT number 2020-001466-11; approval 38/20 of the National Ethics Committee of
Greece, approval IS 028/20 of the National Organization for Medicine of Greece,
ClinicalTrials.gov identifier, NCT04357366). The concept of the SAVE trial was that early
recognition of the risk for the progression of patients with lower respiratory tract
infection (LRTI) by the new coronavirus SARS-CoV-2 into severe respiratory failure (SRF) may
guide anakinra therapy to prevent SRF. The tool that was used for the diagnosis of risk for
SRF is the biomarker suPAR (soluble urokinase plasminogen activator receptor) at measurable
concentrations in the blood ≥6 ng/ml. The trial was designed to be open-label non-randomized
and the idea was το the start of treatment well before any sign of respiratory failure
emerges. Patients hospitalized at tertiary hospitals during the same time period as the SAVE
trial was ongoing and who were receiving the same standard-of-care (SOC) treatment were
studied as comparators. An interim analysis was submitted to the National Organization for
Medicines; number 108002/23.10/2020. In this interim analysis, 130 patients receiving
anakinra treatment and SOC were analysed and they were compared to 130 patients receiving
SOC. The 130 SOC parallel comparators were selected by propensity score matching to be fully
matched to the anakinra-treated patients for age, comorbidities, severity scores on the day
of hospital admission, i.e. APACHE II score, Pneumonia Severity Index (PSI), Sequential Organ
Failure Assessment (SOFA) and WHO severity, and for the intake of azithromycin,
hydroxychloroquine and dexamethasone. SRF was defined as any respiratory ratio (pO2/FiO2)
less than 150 mmHg necessitating mechanical ventilation or non-invasive ventilation (NIV).
The results of this analysis may be summarized as follows:
- The incidence of SRF was significantly decreased from 59.2% in the parallel
standard-of-care (SOC) comparators (n= 130) to 22.3% among the 130 anakinra-treated
patients; hazard ratio, 0.30; 95% confidence intervals 0.20-0.46; P: 4.6 x 10-8.
- 30-day mortality was decreased from 22.3% in the SOC comparators to 11.5% among
anakinra-treated patients; hazard ratio 0.49; 95% confidence intervals 0.25-0.97%; P:
0.041.
- Duration of stay at the intensive care unit was shortened with anakinra treatment
compared to the SOC comparators for the patients who eventually developed SRF
- The median cost of hospitalization was significantly reduced from €2.398,40 among SOC
comparators to €1.291,40 among anakinra-treated patients
- No safety concerns were raised.
Drug: Anakinra
Standard-of-care and anakinra. Anakinra is injected subcutaneously as 100 mg once daily for 10 days
Other Name: Kineret
Drug: Placebo
Standard-of-care and placebo. Placebo is injected subcutaneously once daily for 10 days
Inclusion Criteria:
1. Age equal to or above 18 years
2. Male or female gender
3. In case of women, unwillingness to remain pregnant during the study period.
4. Written informed consent provided by the patient. For subjects without decision-making
capacity, informed consent must be obtained from a legally designated representative
following the national legislation in the Member State where the trial is planned.
5. Confirmed infection by SARS-CoV-2 virus
6. Findings in chest-X-ray or in chest computed tomography compatible with lower
respiratory tract infection
7. Need for hospitalization for COVID-19. The need for hospitalization is defined by the
attending physician taking into consideration clinical presentation, requirement for
supportive care, potential risk factors for severe disease, and conditions at home,
including the presence of vulnerable persons in the household.
8. Plasma suPAR ≥6ng/ml
Exclusion Criteria:
- Age below 18 years
- Denial for written informed consent
- Any stage IV malignancy
- Any do not resuscitate decision
- Αny pO2/FiO2 (partial oxygen pressure to fraction of inspired oxygen) ratio less than
150 mmHg irrespective if the patient is under mechanical ventilation (MV) /
non-invasive ventilation (NIV) / extracorporeal membrane oxygenation (ECMO) or not
- Patient under MV or NIV or ECMO
- Any primary immunodeficiency
- Less than 1,500 neutrophils/mm3
- Plasma suPAR less than 6 ng/ml
- Known hypersensitivity to anakinra
- Oral or IV intake of corticosteroids at a daily dose equal or greater than 0.4 mg/kg
prednisone for a period greater than the last 15 days.
- Any anti-cytokine biological treatment the last one month
- Severe hepatic failure defined as Child-Pugh stage of 3
- End-stage renal failure necessitating hemofiltration or peritoneal hemodialysis
- Pregnancy or lactation. Women of child-bearing potential will be screened by a urine
pregnancy test before inclusion in the study
- Participation in any other interventional trial
2nd Department of Internal Medicine, University General Hospital of Alexandroupolis
Alexandroupolis, Greece
10th Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens
Athens, Greece
1st Department of Internal Medicine, AMALIA FLEMING Prefecture General Hospital of Melissia
Athens, Greece
1st Department of Internal Medicine, General Hospital of Athens KORGIALENIO-BENAKIO E.E.S.
Athens, Greece
1st Department of Internal Medicine, General Hospital of Eleusis THRIASIO
Athens, Greece
1st Department of Internal Medicine, General Hospital of Nea Ionia CONSTANTOPOULIO-PATISION
Athens, Greece
1st Department of Internal Medicine, General Hospital of Voula ASKLEPIEIO
Athens, Greece
1st University Department of Internal Medicine, General Hospital of Athens LAIKO
Athens, Greece
1st University Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens
Athens, Greece
2nd Department of Internal Medicine, General Hospital of Eleusis THRIASIO
Athens, Greece
2nd Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens
Athens, Greece
2nd University Department of Internal Medicine, IPPOKRATEION General Hospital of Athens
Athens, Greece
3rd Department of Internal Medicine, General Hospital of Athens KORGIALENEIO-BENAKEIO E.E.S.
Athens, Greece
3rd University Department of Internal Medicine, General Hospital of Chest Diseases of Athens SOTIRIA
Athens, Greece
4th Department of Internal Medicine, ATTIKON University General Hospital
Athens, Greece
4th Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens
Athens, Greece
5th Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens
Athens, Greece
COVID-19 Department, General Hospital of Attica SISMANOGLEIO-AMALIA FLEMING
Athens, Greece
Department of Clinical Therapeutics, ALEXANDRA General Hospital of Athens
Athens, Greece
Department of COVID-19, Evangelismos General Hospital
Athens, Greece
Department of Internal Medicine, General Hospital of Athens Elpis
Athens, Greece
• 1st Department of Internal Medicine, General Hospital of Athens G. GENNIMATAS
Athens, Greece
• Department of Internal Medicine, General Hospital of Chest Diseases of Athens SOTIRIA
Athens, Greece
Department of Pulmonary Medicine, General Hospital of Kerkyra
Corfu, Greece
1st Department of Internal Medicine, General University Hospital of Ioannina
Ioánnina, Greece
Department of Internal Medicine, University General Hospital of Larissa,
Larissa, Greece
Department of Internal Medicine, University General Hospital of Patras PANAGIA I VOITHIA
Patra, Greece
2nd Department of Internal Medicine, General Hospital of Piraeus TZANEIO
Piraeus, Greece
1st Department of Internal Medicine, AHEPA University General Hospital of Thessaloniki
Thessaloníki, Greece
1st Department of Internal Medicine, PAPAGEORGIOU General Hospital of Thessaloniki
Thessaloníki, Greece
2nd Department of Propedeutic Medicine, Ippokrateion University General Hospital of Thessaloniki
Thessaloníki, Greece
3rd University Department of Internal Medicine, PAPAGEORGIOU General Hospital of Thessaloniki
Thessaloníki, Greece
Dipartimento di Medicina Dipartimento di Malattie Infettive, ASST Spedali civili
Brescia, Italy
Unità Operativa Clinica Malattie Infettive, Ospedale Policlinico San Martino
Genova, Italy
Dipartimento di Medicina Interna, Istituto Clinico Humanitas
Milano, Italy
Medicina Interna, Reumatologia, Immunologia, IRCCS San Raffaele
Milano, Italy
Dipartimento di Malattie Infettive e Tropicali e Microbiologia, IRCCS Ospedale Sacro Cuore Don Calabria
Negrar, Italy
Dipartimento di Malattie Infettive ad alta Intensità di cura ed altamente contagiose, IRCCS Lazzaro Spallanzani
Roma, Italy
Dipartimento Scienze di laboratorio e infettivologiche, Policlinico Universitario Agostino Gemelli
Roma, Italy
Dipartimento di Malattie infettive e tropicali-Università dell'Insubria, ASST dei Sette Laghi
Varese, Italy
Evangelos Giamarellos-Bourboulis, MD, PhD, Study Chair
Hellenic Institute for the Study of Sepsis