Covid19Phase 3SAVE-MORENCT04680949
suPAR-Guided Anakinra Treatment for Management of Severe Respiratory Failure by COVID-19
A Phase 3 study testing Anakinra in people with Covid19, run by Hellenic Institute for the Study of Sepsis at 40 sites in 2 countries.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Covid19
- What is being tested?
- Anakinra
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 606 participants
- Where
- 40 sitesin 2 countries
- Study dates
- 23 Dec 2020to 6 Feb 2022
- Phase
- Phase 3
- 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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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. 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.
- Confirmed infection by SARS-CoV-2 virus
- Findings in chest-X-ray or in chest computed tomography compatible with lower respiratory tract infection
- 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.
- Plasma suPAR ≥6ng/ml
Who cannot join
- 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
Show all 16Show fewer
- 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
Trial locations and contacts
40 sites in 2 countries.
40 sites in 2 countries
Greece32 sites
2nd Department of Internal Medicine, University General Hospital of Alexandroupolis
Alexandroupoli
10th Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens
Athens
1st Department of Internal Medicine, AMALIA FLEMING Prefecture General Hospital of Melissia
Athens
1st Department of Internal Medicine, General Hospital of Athens KORGIALENIO-BENAKIO E.E.S.
Athens
1st Department of Internal Medicine, General Hospital of Eleusis THRIASIO
Athens
1st Department of Internal Medicine, General Hospital of Nea Ionia CONSTANTOPOULIO-PATISION
Athens
1st Department of Internal Medicine, General Hospital of Voula ASKLEPIEIO
Athens
1st University Department of Internal Medicine, General Hospital of Athens LAIKO
Athens
1st University Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens
Athens
2nd Department of Internal Medicine, General Hospital of Eleusis THRIASIO
Athens
2nd Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens
Athens
2nd University Department of Internal Medicine, IPPOKRATEION General Hospital of Athens
Athens
3rd Department of Internal Medicine, General Hospital of Athens KORGIALENEIO-BENAKEIO E.E.S.
Athens
3rd University Department of Internal Medicine, General Hospital of Chest Diseases of Athens SOTIRIA
Athens
4th Department of Internal Medicine, ATTIKON University General Hospital
Athens
4th Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens
Athens
5th Department of Pulmonary Medicine, SOTIRIA General Hospital of Chest Diseases of Athens
Athens
COVID-19 Department, General Hospital of Attica SISMANOGLEIO-AMALIA FLEMING
Athens
Department of Clinical Therapeutics, ALEXANDRA General Hospital of Athens
Athens
Department of COVID-19, Evangelismos General Hospital
Athens
Department of Internal Medicine, General Hospital of Athens Elpis
Athens
• 1st Department of Internal Medicine, General Hospital of Athens G. GENNIMATAS
Athens
• Department of Internal Medicine, General Hospital of Chest Diseases of Athens SOTIRIA
Athens
Department of Pulmonary Medicine, General Hospital of Kerkyra
Corfu
1st Department of Internal Medicine, General University Hospital of Ioannina
Ioannina
Department of Internal Medicine, University General Hospital of Larissa,
Larissa
Department of Internal Medicine, University General Hospital of Patras PANAGIA I VOITHIA
Pátrai
2nd Department of Internal Medicine, General Hospital of Piraeus TZANEIO
Piraeus
1st Department of Internal Medicine, AHEPA University General Hospital of Thessaloniki
Thessaloniki
1st Department of Internal Medicine, PAPAGEORGIOU General Hospital of Thessaloniki
Thessaloniki
2nd Department of Propedeutic Medicine, Ippokrateion University General Hospital of Thessaloniki
Thessaloniki
3rd University Department of Internal Medicine, PAPAGEORGIOU General Hospital of Thessaloniki
Thessaloniki
Italy8 sites
Dipartimento di Medicina Dipartimento di Malattie Infettive, ASST Spedali civili
Brescia
Unità Operativa Clinica Malattie Infettive, Ospedale Policlinico San Martino
Genova
Dipartimento di Medicina Interna, Istituto Clinico Humanitas
Milan
Medicina Interna, Reumatologia, Immunologia, IRCCS San Raffaele
Milan
Dipartimento di Malattie Infettive e Tropicali e Microbiologia, IRCCS Ospedale Sacro Cuore Don Calabria
Negrar
Dipartimento di Malattie Infettive ad alta Intensità di cura ed altamente contagiose, IRCCS Lazzaro Spallanzani
Roma
Dipartimento Scienze di laboratorio e infettivologiche, Policlinico Universitario Agostino Gemelli
Roma
Dipartimento di Malattie infettive e tropicali-Università dell'Insubria, ASST dei Sette Laghi
Varese
About this study
Official title: suPAR-Guided Anakinra Treatment for Validation of the Risk and Early Management of Severe Respiratory Failure by COVID-19: The SAVE-MORE Double-blind, Randomized, Phase III Confirmatory Trial
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).
Read the detailed description
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.
- Conditions
- Covid19
- Being tested
- Anakinra, Placebo
- Keywords
- SARS-CoV 2, anakinra
- Medical subject headings
- COVID-19
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AnakinraDrug
Also called Kineret
Standard-of-care and anakinra. Anakinra is injected subcutaneously as 100 mg once daily for 10 days
PlaceboDrug
Standard-of-care and placebo. Placebo is injected subcutaneously once daily for 10 days
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | Patients receiving standard-of-care (SOC) and placebo. Placebo is injected subcutaneously once daily for 10 days Receives: Drug: Placebo |
| Anakinra | Experimental | Patients receiving SOC and anakinra. Anakinra is injected subcutaneously as 100 mg once daily for 10 days Receives: Drug: Anakinra |
What is being measured
The primary outcome is the main question the study is designed to answer.
Comparison of the distribution of frequencies of each score of a 5-scale patient state evaluated from the 11-point WHO Clinical Progression ordinal Scale (CPS) between the two arms of treatment
Comparison of the distribution of frequencies of each score of the 5-scale patient state evaluated from the 11-point WHO Clinical Progression ordinal Scale (CPS) between the two arms of treatment by Day 28. This will be expressed as the distribution of the frequencies of each score of the scale in each arm of treatment by Day 28. The scale ranges from 0 (best outcome-asymptomatic) to 11 (worst outcome-death).
Measured: 28 days
Secondary outcomes (22)
Absolute change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS)
Comparison of the absolute change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS) between the two arms of treatment. The scale ranges from 0 (best outcome-asymptomatic) to 11 (worst outcome-death).
Measured: 28 days
Relative change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS)
Comparison of the relative change (%) of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS) between the two arms of treatment. The scale ranges from 0 (best outcome-asymptomatic) to 11 (worst outcome-death).
Measured: 28 days
Absolute change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS)
Comparison of the absolute change of the measure of the 11-point of WHO Clinical Progression nordinal Scale (CPS) between the two arms of treatment. The scale ranges from 0 (best outcome-asymptomatic) to 11 (worst outcome-death).
Measured: 14 days
Relative change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS)
Comparison of the relative (%) change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS) between the two arms of treatment. The scale ranges from 0 (best outcome-asymptomatic) to 11 (worst outcome-death).
Measured: 14 days
Absolute change of the SOFA score
Comparison of the absolute change of the SOFA score (in points) between the two arms of treatment
Measured: 14 days
Relative change of the SOFA score
Comparison of the relative (%) change of the SOFA score (in points) between the two arms of treatment
Measured: 14 days
Absolute change of the SOFA score
Comparison of the absolute change of the SOFA score between the two arms of treatment
Measured: 7 days
Relative change of the SOFA score
Comparison of the relative (%) change of the SOFA score between the two arms of treatment
Measured: 7 days
Time until hospital discharge
Comparison of the time until hospital discharge between the two arms of treatment
Measured: 90 days
Time until discharge from the intensive care unit
Comparison of the time until discharge from the intensive care unit between the two arms of treatment
Measured: 90 days
Comparison of the rate of serious and non-serious adverse events between the two arms of treatment
Comparison of the rate of serious and non-serious adverse events between the two arms of treatment
Measured: 90 days
Comparison of the rate of serious and non-serious adverse events between the two arms of treatment
Comparison of the rate of serious and non-serious adverse events between the two arms of treatment
Measured: 60 days
Relative changes of circulating concentrations of suPAR (μg/liter), D-dimers (μg/liter), ferritin (μg/liter), and Interleukin-6 (μg/liter) by Day 7 from baseline Day 1
Comparison of the relative changes of circulating concentrations of suPAR (μg/liter),D-dimers (μg/liter), ferritin (μg/liter), and Interleukin-6 (μg/liter) between the two arms of treatment
Measured: 7 days
Relative changes of circulating concentrations of C-reactive protein (mg/liter) by Day 7 from baseline Day 1
Comparison of the relative changes of circulating concentrations of C-reactive protein (mg/liter) between the two arms of treatment
Measured: 7 days
Relative changes of circulating concentrations of suPAR (μg/liter),D-dimers (μg/liter), ferritin (μg/liter), and Interleukin-6 (μg/liter) by Day 4 from baseline Day 1
Comparison of the relative changes of circulating concentrations of suPAR (μg/liter),D-dimers (μg/liter), ferritin (μg/liter), and Interleukin-6 (μg/liter) between the two arms of treatment
Measured: 4 days
Relative changes of circulating concentrations of C-reactive protein (mg/liter) by Day 4 from baseline Day 1
Comparison of the relative changes of circulating concentrations of C-reactive protein (mg/liter) between the two arms of treatment
Measured: 4 days
Absolute change of the viral load by Day 7 from baseline Day 1
Comparison of the absolute change of the viral load (in copies) between the two arms of treatment
Measured: 7 days
Relative change of the viral load by Day 7 from baseline Day 1
Comparison of the relative (%) change of the viral load between the two arms of treatment
Measured: 7 days
Absolute change of the viral load by Day 4 from baseline Day 1
Comparison of the absolute change of the viral load (in copies) between the two arms of treatment
Measured: 4 days
relative change of the viral load by Day 4 from baseline Day 1
Comparison of the relative change (%) of the viral load between the two arms of treatment
Measured: 4 days
Transcriptomic analysis
Expression of messenger Ribonucleic Acid (mRNA) will be compared between the two arms of treatment
Measured: 7 days
Proteomic analysis
Protein composition will be compared between the two arms of treatment
Measured: 7 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Dec 2020
- Study start23 Dec 2020
- Primary completion31 Mar 2021
- Study completion6 Feb 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Covid19Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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 WHO clinical progression scale (CPS).
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 606 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hellenic Institute for the Study of Sepsis
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Evangelos Giamarellos-Bourboulis, MD, PhD, Study chair, Hellenic Institute for the Study of Sepsis
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04680949
- Sponsor's protocol ID
- SAVE-MORE
- Acronym
- SAVE-MORE
- Status last verified
- Sep 2022
- First submitted
- 18 Dec 2020
- Last updated
- 6 Sep 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Kyriazopoulou E, Kotsaki A, Safarika A, Poulakou G, Milionis H, Metallidis S, Adamis G, Fragkou A, Rapti A, Del Vecchio P, Kalomenidis I, Kitzoglou D, Angheben A, Kainis I, Iliopoulou K, Serino FS, Bakakos P, Tzavara V, Ioannou S, Dagna L, Dimakou K, Tzatzagou G, Chini M, Bassetti M, Kotsis V, Tsoukalas G, Selmi C, Nikolakopoulou S, Samarkos M, Doumas M, Masgala A, Papanikolaou I, Argyraki A, Akinosoglou K, Symbardi S, Panagopoulos P, Dalekos GN, Liesenfeld O, Sweeney TE, Khatri P, Giamarellos-Bourboulis EJ. 29-mRNA host response signatures for classification of bacterial infection, viral infection and disease progression in COVID-19 pneumonia: a post hoc analysis of the SAVE-MORE randomized clinical trial. Intensive Care Med Exp. 2025 Jun 30;13(1):67. doi: 10.1186/s40635-025-00777-1.
PubMed 40583075Kyriazopoulou E, Hasin-Brumshtein Y, Midic U, Poulakou G, Milionis H, Metallidis S, Astriti M, Fragkou A, Rapti A, Taddei E, Kalomenidis I, Chrysos G, Angheben A, Kainis I, Alexiou Z, Castelli F, Serino FS, Bakakos P, Nicastri E, Tzavara V, Ioannou S, Dagna L, Dimakou K, Tzatzagou G, Chini M, Bassetti M, Kotsis V, Tsoukalas DG, Selmi C, Konstantinou A, Samarkos M, Doumas M, Masgala A, Pagkratis K, Argyraki A, Akinosoglou K, Symbardi S, Netea MG, Panagopoulos P, Dalekos GN, Liesenfeld O, Sweeney TE, Khatri P, Giamarellos-Bourboulis EJ. Transitions of blood immune endotypes and improved outcome by anakinra in COVID-19 pneumonia: an analysis of the SAVE-MORE randomized controlled trial. Crit Care. 2024 Mar 12;28(1):73. doi: 10.1186/s13054-024-04852-z.
PubMed 38475786Akinosoglou K, Kotsaki A, Gounaridi IM, Christaki E, Metallidis S, Adamis G, Fragkou A, Fantoni M, Rapti A, Kalomenidis I, Chrysos G, Boni G, Kainis I, Alexiou Z, Castelli F, Serino FS, Bakakos P, Nicastri E, Tzavara V, Safarika A, Ioannou S, Dagna L, Dimakou K, Tzatzagou G, Chini M, Bassetti M, Kotsis V, Angheben A, Tsoukalas G, Selmi C, Spiropoulou OM, Samarkos M, Doumas M, Damoraki G, Masgala A, Papanikolaou I, Argyraki A, Negri M, Leventogiannis K, Sympardi S, Gatselis NK, Petrakis V, Netea MG, Panagopoulos P, Sakka V, Milionis H, Dalekos GN, Giamarellos-Bourboulis EJ. Efficacy and safety of early soluble urokinase plasminogen receptor plasma-guided anakinra treatment of COVID-19 pneumonia: A subgroup analysis of the SAVE-MORE randomised trial. EClinicalMedicine. 2023 Feb;56:101785. doi: 10.1016/j.eclinm.2022.101785. Epub 2022 Dec 26.
PubMed 36590789Samaras C, Kyriazopoulou E, Poulakou G, Reiner E, Kosmidou M, Karanika I, Petrakis V, Adamis G, Gatselis NK, Fragkou A, Rapti A, Taddei E, Kalomenidis I, Chrysos G, Bertoli G, Kainis I, Alexiou Z, Castelli F, Saverio Serino F, Bakakos P, Nicastri E, Tzavara V, Kostis E, Dagna L, Koukidou S, Tzatzagou G, Chini M, Bassetti M, Trakatelli C, Tsoukalas G, Selmi C, Samarkos M, Pyrpasopoulou A, Masgala A, Antonakis E, Argyraki A, Akinosoglou K, Sympardi S, Panagopoulos P, Milionis H, Metallidis S, Syrigos KN, Angel A, Dalekos GN, Netea MG, Giamarellos-Bourboulis EJ. Interferon gamma-induced protein 10 (IP-10) for the early prognosis of the risk for severe respiratory failure and death in COVID-19 pneumonia. Cytokine. 2023 Feb;162:156111. doi: 10.1016/j.cyto.2022.156111. Epub 2022 Dec 14.
PubMed 36529030
Study at a glance
From the registry record, last updated by the sponsor on 6 Sep 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- suPAR-Guided Anakinra Treatment for Validation of the Risk and Early Management of Severe Respiratory Failure by COVID-19: The SAVE-MORE Double-blind, Randomized, Phase III Confirmatory Trial
- ClinicalTrials.gov ID
- NCT04680949
- Acronym / sponsor ID
- SAVE-MORE / SAVE-MORE
- Conditions
- Covid19
- Keywords
- SARS-CoV 2, anakinra
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 606 participants (actual)
- Lead sponsor
- Hellenic Institute for the Study of SepsisUniversity, hospital or other
- Study start
- 23 Dec 2020 (actual)
- Primary completion
- 31 Mar 2021 (actual)
- Study completion
- 6 Feb 2022 (actual)
- First posted
- 23 Dec 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- 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 WHO clinical progression scale (CPS).
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: PlaceboPatients receiving standard-of-care (SOC) and placebo. Placebo is injected subcutaneously once daily for 10 days |
| Anakinra | Experimental | Drug: AnakinraPatients receiving SOC and anakinra. Anakinra is injected subcutaneously as 100 mg once daily for 10 days |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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. 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.
- Confirmed infection by SARS-CoV-2 virus
Key exclusion criteria (16 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AnakinraAlso: KineretStandard-of-care and anakinra. Anakinra is injected subcutaneously as 100 mg once daily for 10 days | Drug | Anakinra |
| PlaceboStandard-of-care and placebo. Placebo is injected subcutaneously once daily for 10 days | Drug | Placebo |
Primary outcome
Comparison of the distribution of frequencies of each score of a 5-scale patient state evaluated from the 11-point WHO Clinical Progression ordinal Scale (CPS) between the two arms of treatment
Time frame: 28 days
Comparison of the distribution of frequencies of each score of the 5-scale patient state evaluated from the 11-point WHO Clinical Progression ordinal Scale (CPS) between the two arms of treatment by Day 28. This will be expressed as the distribution of the frequencies of each score of the scale in each arm of treatment by Day 28. The scale ranges from 0 (best outcome-asymptomatic) to 11 (worst outcome-death).
22 secondary outcomes
Absolute change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS)
Time frame: 28 days
Relative change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS)
Time frame: 28 days
Absolute change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS)
Time frame: 14 days
Relative change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS)
Time frame: 14 days
Absolute change of the SOFA score
Time frame: 14 days
Relative change of the SOFA score
Time frame: 14 days
Absolute change of the SOFA score
Time frame: 7 days
Relative change of the SOFA score
Time frame: 7 days
Time until hospital discharge
Time frame: 90 days
Time until discharge from the intensive care unit
Time frame: 90 days
Comparison of the rate of serious and non-serious adverse events between the two arms of treatment
Time frame: 90 days
Comparison of the rate of serious and non-serious adverse events between the two arms of treatment
Time frame: 60 days
Relative changes of circulating concentrations of suPAR (μg/liter), D-dimers (μg/liter), ferritin (μg/liter), and Interleukin-6 (μg/liter) by Day 7 from baseline Day 1
Time frame: 7 days
Relative changes of circulating concentrations of C-reactive protein (mg/liter) by Day 7 from baseline Day 1
Time frame: 7 days
Relative changes of circulating concentrations of suPAR (μg/liter),D-dimers (μg/liter), ferritin (μg/liter), and Interleukin-6 (μg/liter) by Day 4 from baseline Day 1
Time frame: 4 days
Relative changes of circulating concentrations of C-reactive protein (mg/liter) by Day 4 from baseline Day 1
Time frame: 4 days
Absolute change of the viral load by Day 7 from baseline Day 1
Time frame: 7 days
Relative change of the viral load by Day 7 from baseline Day 1
Time frame: 7 days
Absolute change of the viral load by Day 4 from baseline Day 1
Time frame: 4 days
relative change of the viral load by Day 4 from baseline Day 1
Time frame: 4 days
Transcriptomic analysis
Time frame: 7 days
Proteomic analysis
Time frame: 7 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Sep 2022.
- Derived from this study: PubMed 40583075Kyriazopoulou E, Kotsaki A, Safarika A, Poulakou G, Milionis H, Metallidis S, Adamis G, Fragkou A, Rapti A, Del Vecchio P, Kalomenidis I, Kitzoglou D, Angheben A, Kainis I, Iliopoulou K, Serino FS, Bakakos P, Tzavara V, Ioannou S, Dagna L, Dimakou K, Tzatzagou G, Chini M, Bassetti M, Kotsis V, Tsoukalas G, Selmi C, Nikolakopoulou S, Samarkos M, Doumas M, Masgala A, Papanikolaou I, Argyraki A, Akinosoglou K, Symbardi S, Panagopoulos P, Dalekos GN, Liesenfeld O, Sweeney TE, Khatri P, Giamarellos-Bourboulis EJ. 29-mRNA host response signatures for classification of bacterial infection, viral infection and disease progression in COVID-19 pneumonia: a post hoc analysis of the SAVE-MORE randomized clinical trial. Intensive Care Med Exp. 2025 Jun 30;13(1):67. doi: 10.1186/s40635-025-00777-1.
- Derived from this study: PubMed 38475786Kyriazopoulou E, Hasin-Brumshtein Y, Midic U, Poulakou G, Milionis H, Metallidis S, Astriti M, Fragkou A, Rapti A, Taddei E, Kalomenidis I, Chrysos G, Angheben A, Kainis I, Alexiou Z, Castelli F, Serino FS, Bakakos P, Nicastri E, Tzavara V, Ioannou S, Dagna L, Dimakou K, Tzatzagou G, Chini M, Bassetti M, Kotsis V, Tsoukalas DG, Selmi C, Konstantinou A, Samarkos M, Doumas M, Masgala A, Pagkratis K, Argyraki A, Akinosoglou K, Symbardi S, Netea MG, Panagopoulos P, Dalekos GN, Liesenfeld O, Sweeney TE, Khatri P, Giamarellos-Bourboulis EJ. Transitions of blood immune endotypes and improved outcome by anakinra in COVID-19 pneumonia: an analysis of the SAVE-MORE randomized controlled trial. Crit Care. 2024 Mar 12;28(1):73. doi: 10.1186/s13054-024-04852-z.
- Derived from this study: PubMed 36590789Akinosoglou K, Kotsaki A, Gounaridi IM, Christaki E, Metallidis S, Adamis G, Fragkou A, Fantoni M, Rapti A, Kalomenidis I, Chrysos G, Boni G, Kainis I, Alexiou Z, Castelli F, Serino FS, Bakakos P, Nicastri E, Tzavara V, Safarika A, Ioannou S, Dagna L, Dimakou K, Tzatzagou G, Chini M, Bassetti M, Kotsis V, Angheben A, Tsoukalas G, Selmi C, Spiropoulou OM, Samarkos M, Doumas M, Damoraki G, Masgala A, Papanikolaou I, Argyraki A, Negri M, Leventogiannis K, Sympardi S, Gatselis NK, Petrakis V, Netea MG, Panagopoulos P, Sakka V, Milionis H, Dalekos GN, Giamarellos-Bourboulis EJ. Efficacy and safety of early soluble urokinase plasminogen receptor plasma-guided anakinra treatment of COVID-19 pneumonia: A subgroup analysis of the SAVE-MORE randomised trial. EClinicalMedicine. 2023 Feb;56:101785. doi: 10.1016/j.eclinm.2022.101785. Epub 2022 Dec 26.
- Derived from this study: PubMed 36529030Samaras C, Kyriazopoulou E, Poulakou G, Reiner E, Kosmidou M, Karanika I, Petrakis V, Adamis G, Gatselis NK, Fragkou A, Rapti A, Taddei E, Kalomenidis I, Chrysos G, Bertoli G, Kainis I, Alexiou Z, Castelli F, Saverio Serino F, Bakakos P, Nicastri E, Tzavara V, Kostis E, Dagna L, Koukidou S, Tzatzagou G, Chini M, Bassetti M, Trakatelli C, Tsoukalas G, Selmi C, Samarkos M, Pyrpasopoulou A, Masgala A, Antonakis E, Argyraki A, Akinosoglou K, Sympardi S, Panagopoulos P, Milionis H, Metallidis S, Syrigos KN, Angel A, Dalekos GN, Netea MG, Giamarellos-Bourboulis EJ. Interferon gamma-induced protein 10 (IP-10) for the early prognosis of the risk for severe respiratory failure and death in COVID-19 pneumonia. Cytokine. 2023 Feb;162:156111. doi: 10.1016/j.cyto.2022.156111. Epub 2022 Dec 14.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Evangelos Giamarellos-Bourboulis, MD, PhD study chair
Hellenic Institute for the Study of Sepsis
40 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Anakinra in people with Covid19, run by Hellenic Institute for the Study of Sepsis at 40 sites in 2 countries.
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 8 inclusion and 16 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 6 Sep 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 40 sites in Greece, Italy. 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
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?
Comparison of the distribution of frequencies of each score of a 5-scale patient state evaluated from the 11-point WHO Clinical Progression ordinal Scale (CPS) between the two arms of treatment (time frame: 28 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 NCT04680949, which also lists 4 linked publications.
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 6 Sep 2022.