suPAR-Guided Anakinra Treatment for Management of Severe Respiratory Failure by COVID-19 (SAVE-MORE)

• ClinicalTrials.gov Identifier: NCT04680949
• Recruitment Status: Completed
• First Posted: December 23, 2020
• Last Update Posted: September 6, 2022
• Sponsor: Hellenic Institute for the Study of Sepsis
• Information provided by (Responsible Party): Hellenic Institute for the Study of Sepsis

Tracking Information

• First Submitted Date: December 18, 2020
• First Posted Date: December 23, 2020
• Last Update Posted Date: September 6, 2022
• Actual Study Start Date: December 23, 2020
• Actual Primary Completion Date: March 31, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 22, 2020)

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).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 22, 2020)

• Absolute change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS) [ Time Frame: 28 days ]
  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).
• Relative change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS) [ Time Frame: 28 days ]
  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).
• Absolute change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS) [ Time Frame: 14 days ]
  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).
• Relative change of the measure of the 11-point of WHO Clinical Progression ordinal Scale (CPS) [ Time Frame: 14 days ]
  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).
• Absolute change of the SOFA score [ Time Frame: 14 days ]
  Comparison of the absolute change of the SOFA score (in points) between the two arms of treatment
• Relative change of the SOFA score [ Time Frame: 14 days ]
  Comparison of the relative (%) change of the SOFA score (in points) between the two arms of treatment
• Absolute change of the SOFA score [ Time Frame: 7 days ]
  Comparison of the absolute change of the SOFA score between the two arms of treatment
• Relative change of the SOFA score [ Time Frame: 7 days ]
  Comparison of the relative (%) change of the SOFA score between the two arms of treatment
• Time until hospital discharge [ Time Frame: 90 days ]
  Comparison of the time until hospital discharge between the two arms of treatment
• Time until discharge from the intensive care unit [ Time Frame: 90 days ]
  Comparison of the time until discharge from the intensive care unit between the two arms of treatment
• 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
• Comparison of the rate of serious and non-serious adverse events between the two arms of treatment [ Time Frame: 60 days ]
  Comparison of the rate of serious and non-serious adverse events between the two arms of treatment
• 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 ]
  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
• Relative changes of circulating concentrations of C-reactive protein (mg/liter) by Day 7 from baseline Day 1 [ Time Frame: 7 days ]
  Comparison of the relative changes of circulating concentrations of C-reactive protein (mg/liter) between the two arms of treatment
• 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 ]
  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
• Relative changes of circulating concentrations of C-reactive protein (mg/liter) by Day 4 from baseline Day 1 [ Time Frame: 4 days ]
  Comparison of the relative changes of circulating concentrations of C-reactive protein (mg/liter) between the two arms of treatment
• Absolute change of the viral load by Day 7 from baseline Day 1 [ Time Frame: 7 days ]
  Comparison of the absolute change of the viral load (in copies) between the two arms of treatment
• Relative change of the viral load by Day 7 from baseline Day 1 [ Time Frame: 7 days ]
  Comparison of the relative (%) change of the viral load between the two arms of treatment
• Absolute change of the viral load by Day 4 from baseline Day 1 [ Time Frame: 4 days ]
  Comparison of the absolute change of the viral load (in copies) between the two arms of treatment
• relative change of the viral load by Day 4 from baseline Day 1 [ Time Frame: 4 days ]
  Comparison of the relative change (%) of the viral load between the two arms of treatment
• Transcriptomic analysis [ Time Frame: 7 days ]
  Expression of messenger Ribonucleic Acid (mRNA) will be compared between the two arms of treatment
• Proteomic analysis [ Time Frame: 7 days ]
  Protein composition will be compared between the two arms of treatment

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: December 22, 2020)

• Cost of hospitalization [ Time Frame: 90 days ]
  Comparison of the cost of hospitalization between the two arms of treatment
• Comparison of the distribution of frequencies of each score of a 5-scale patient state [ Time Frame: 60 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 60. The scale ranges from 0 (best outcome outpatients) to 5 (worst outcome-death)
• Comparison of the distribution of frequencies of each score of a 5-scale patient state [ Time Frame: 90 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 90. The scale ranges from ) (best outcome-outpatients) to 5 (worst outcome-death)

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: suPAR-Guided Anakinra Treatment for Management of Severe Respiratory Failure by COVID-19
• 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
• Brief 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 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 Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

double-blind trial

Primary Purpose: Treatment

• Condition: Covid19

Intervention

• 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

Study Arms

• Placebo Comparator: Placebo
  Patients receiving standard-of-care (SOC) and placebo. Placebo is injected subcutaneously once daily for 10 days
  Intervention: Drug: Placebo
• Experimental: Anakinra
  Patients receiving SOC and anakinra. Anakinra is injected subcutaneously as 100 mg once daily for 10 days
  Intervention: Drug: Anakinra

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 2, 2021): 606
• Original Estimated Enrollment (submitted: December 22, 2020): 600
• Actual Study Completion Date: February 6, 2022
• Actual Primary Completion Date: March 31, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Greece, Italy

Administrative Information

• NCT Number: NCT04680949
• Other Study ID Numbers: SAVE-MORE
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hellenic Institute for the Study of Sepsis
• Original Responsible Party: Same as current
• Current Study Sponsor: Hellenic Institute for the Study of Sepsis
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Chair: Evangelos Giamarellos-Bourboulis, MD, PhD; Hellenic Institute for the Study of Sepsis

• PRS Account: Hellenic Institute for the Study of Sepsis
• Verification Date: September 2022