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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2020-005828-11
    Trial protocol
    		 GR   IT  
    Global end of trial date
    28 Jun 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Feb 2024
    First version publication date
    01 Feb 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    SAVE-MORE
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04680949
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hellenic Institute for the Study of Sepsis
    Sponsor organisation address
    Laodikeias 17 str., Athens, Greece, 11528
    Public contact
    President of the Board, Hellenic Institute for the Study of Sepsis, 0030 2107480662, info@sepsis.gr
    Scientific contact
    President of the Board, Hellenic Institute for the Study of Sepsis, 0030 2107480662, info@sepsis.gr
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Dec 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the 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 WHO clinical progression scale (CPS).
    Protection of trial subjects
    Patients were hospitalized during the trial and were closely monitored by follow-up calls when discharged until the completion of the trial period.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Dec 2020
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Greece: 528
    Country: Number of subjects enrolled
    Italy: 66
    Worldwide total number of subjects
    594
    EEA total number of subjects
    594
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    344
    From 65 to 84 years
    238
    85 years and over
    12

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was performed in 37 research sites, 29 in Greece and 8 in Italy. Recruitment begun from 27 December 2020 and the follow up period was concluded at 28 June 2021. In total, 606 patients were enrolled (194 patients in Treatment Arm 1 and 412 in Treatment arm 2).

    Pre-assignment
    Screening details
    		 A set of inclusion criteria needed to be met for patient enrolment, including confirmed SARS-CoV-2 infection and suPAR level over 6 ng/ml among others. Patients who met any of the exclusion criteria were not enrolled in the study.

    Pre-assignment period milestones
    Number of subjects started
    		 594
    Number of subjects completed
    		 594

    Period 1
    Period 1 title
    Follow-Up Day 28
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Placebo was administered using syringes of the same appearance as the anakinra syringes. All syringes were prepared by the unblinded pharmacist for s.c. injection. The outer part of each syringe was covered to conceal the identity of the study drug, labelled with a unique alphanumeric code, and delivered to the blinded pharmacist and nurse for administration.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment Arm 1
    Arm description
    		 0.67 mL of 0.9% sodium chloride, administered s.c. once daily for 10 days
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sodium chloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in vial
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.67 ml s.c. once daily

    Arm title
    		 Treatment Arm 2
    Arm description
    		 Anakinra 100 mg (0.67 mL) in a prefilled syringe, administered s.c. once daily for 10 days
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Anakinra
    Investigational medicinal product code
    Other name
    Kineret
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    100 mg s.c once daily

    Number of subjects in period 1
    		Treatment Arm 1 Treatment Arm 2
    Started
    189
    405
    Completed
    189
    405
    Period 2
    Period 2 title
    Follow-Up Day 14
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Placebo was administered using syringes of the same appearance as the anakinra syringes. All syringes were prepared by the unblinded pharmacist for s.c. injection. The outer part of each syringe was covered to conceal the identity of the study drug, labelled with a unique alphanumeric code, and delivered to the blinded pharmacist and nurse for administration.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment Arm 1
    Arm description
    		 0.67 mL of 0.9% sodium chloride, administered s.c. once daily for 10 days
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sodium chloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in vial
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.67 ml s.c. once daily

    Arm title
    		 Treatment Arm 2
    Arm description
    		 Anakinra 100 mg (0.67 mL) in a prefilled syringe, administered s.c. once daily for 10 days
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Anakinra
    Investigational medicinal product code
    Other name
    Kineret
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    100 mg s.c once daily

    Number of subjects in period 2
    		Treatment Arm 1 Treatment Arm 2
    Started
    189
    405
    Completed
    189
    405
    Period 3
    Period 3 title
    Follow-Up Day 7 - Hospitalized
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Placebo was administered using syringes of the same appearance as the anakinra syringes. All syringes were prepared by the unblinded pharmacist for s.c. injection. The outer part of each syringe was covered to conceal the identity of the study drug, labelled with a unique alphanumeric code, and delivered to the blinded pharmacist and nurse for administration.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment Arm 1
    Arm description
    		 0.67 mL of 0.9% sodium chloride, administered s.c. once daily for 10 days
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sodium chloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in vial
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.67 ml s.c. once daily

    Arm title
    		 Treatment Arm 2
    Arm description
    		 Anakinra 100 mg (0.67 mL) in a prefilled syringe, administered s.c. once daily for 10 days
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Anakinra
    Investigational medicinal product code
    Other name
    Kineret
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    100 mg s.c once daily

    Number of subjects in period 3
    		Treatment Arm 1 Treatment Arm 2
    Started
    189
    405
    Completed
    184
    392
    Not completed
    5
    13
         No longer hospitalized
    5
    13
    Period 4
    Period 4 title
    Follow-Up Day 60
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Placebo was administered using syringes of the same appearance as the anakinra syringes. All syringes were prepared by the unblinded pharmacist for s.c. injection. The outer part of each syringe was covered to conceal the identity of the study drug, labelled with a unique alphanumeric code, and delivered to the blinded pharmacist and nurse for administration.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment Arm 1
    Arm description
    		 0.67 mL of 0.9% sodium chloride, administered s.c. once daily for 10 days
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sodium chloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in vial
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.67 ml s.c. once daily

    Arm title
    		 Treatment Arm 2
    Arm description
    		 Anakinra 100 mg (0.67 mL) in a prefilled syringe, administered s.c. once daily for 10 days
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Anakinra
    Investigational medicinal product code
    Other name
    Kineret
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    100 mg s.c once daily

    Number of subjects in period 4 [1]
    		Treatment Arm 1 Treatment Arm 2
    Started
    183
    392
    Completed
    183
    392
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The number of patients in the period in question (Follow-Up Day 60) is lower since several patients were lost to follow-up. More precisely, for Follow-up Day 60, the data of 183 Patients of Arm1, and 392 Patients of Arm 2 were available i.e. 6 and 14 patients respectively were lost to follow-up.
    Period 5
    Period 5 title
    Follow-Up Day 90
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Placebo was administered using syringes of the same appearance as the anakinra syringes. All syringes were prepared by the unblinded pharmacist for s.c. injection. The outer part of each syringe was covered to conceal the identity of the study drug, labelled with a unique alphanumeric code, and delivered to the blinded pharmacist and nurse for administration.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment Arm 1
    Arm description
    		 0.67 mL of 0.9% sodium chloride, administered s.c. once daily for 10 days
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sodium chloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in vial
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.67 ml s.c. once daily

    Arm title
    		 Treatment Arm 2
    Arm description
    		 Anakinra 100 mg (0.67 mL) in a prefilled syringe, administered s.c. once daily for 10 days
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Anakinra
    Investigational medicinal product code
    Other name
    Kineret
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    100 mg s.c once daily

    Number of subjects in period 5 [2]
    		Treatment Arm 1 Treatment Arm 2
    Started
    179
    388
    Completed
    179
    388
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The number of patients in the period in question (Follow-Up Day 90) is lower since several patients were lost to follow-up. More precisely, for Follow-up Day 60, the data of 179 Patients of Arm1, and 388 Patients of Arm 2 were available i.e. 10 and 16 patients respectively were lost to follow-up.
    Period 6
    Period 6 title
    Follow-Up Day 14 - Hospitalized
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Placebo was administered using syringes of the same appearance as the anakinra syringes. All syringes were prepared by the unblinded pharmacist for s.c. injection. The outer part of each syringe was covered to conceal the identity of the study drug, labelled with a unique alphanumeric code, and delivered to the blinded pharmacist and nurse for administration.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment Arm 1
    Arm description
    		 0.67 mL of 0.9% sodium chloride, administered s.c. once daily for 10 days
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sodium chloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in vial
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.67 ml s.c. once daily

    Arm title
    		 Treatment Arm 2
    Arm description
    		 Anakinra 100 mg (0.67 mL) in a prefilled syringe, administered s.c. once daily for 10 days
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Anakinra
    Investigational medicinal product code
    Other name
    Kineret
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    100 mg s.c once daily

    Number of subjects in period 6 [3]
    		Treatment Arm 1 Treatment Arm 2
    Started
    66
    120
    Completed
    66
    120
    Notes
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: According to the statistical analysis plan, this variable is analysed only for patients still hospitalised by Day 14. The reason is that for patients who had been discharged from the hospital before Day 14, the SOFA score cannot be calculated.
    Period 7
    Period 7 title
    Follow-Up Intensive care unit
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Placebo was administered using syringes of the same appearance as the anakinra syringes. All syringes were prepared by the unblinded pharmacist for s.c. injection. The outer part of each syringe was covered to conceal the identity of the study drug, labelled with a unique alphanumeric code, and delivered to the blinded pharmacist and nurse for administration.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment Arm 1
    Arm description
    		 0.67 mL of 0.9% sodium chloride, administered s.c. once daily for 10 days
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sodium chloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in vial
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.67 ml s.c. once daily

    Arm title
    		 Treatment Arm 2
    Arm description
    		 Anakinra 100 mg (0.67 mL) in a prefilled syringe, administered s.c. once daily for 10 days
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Anakinra
    Investigational medicinal product code
    Other name
    Kineret
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    100 mg s.c once daily

    Number of subjects in period 7 [4]
    		Treatment Arm 1 Treatment Arm 2
    Started
    31
    39
    Completed
    31
    39
    Notes
    [4] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: This period included only the patients who were admitted in the ICU. No patients were in the ICU at baseline. Overall, 31 (16.4%) patients in Arm 1 were admitted in the ICU compared to 39 (9.6%) patients in Arm 2.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Treatment Arm 1
    Reporting group description
    		 0.67 mL of 0.9% sodium chloride, administered s.c. once daily for 10 days

    Reporting group title
    Treatment Arm 2
    Reporting group description
    		 Anakinra 100 mg (0.67 mL) in a prefilled syringe, administered s.c. once daily for 10 days

    Reporting group values
    		 Treatment Arm 1 Treatment Arm 2 Total
    Number of subjects
    		 189 405 594
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 111 233 344
        From 65-84 years
    		 75 163 238
        85 years and over
    		 3 9 12
    Age continuous
    Τhe mean age of patients in the FAS was 61.9 years
    Units: years
        arithmetic mean (standard deviation)
    		 61.5 ( 11.3 ) 62 ( 11.4 ) -
    Gender categorical
    57.9% of patients were male and 42.1% were female.
    Units: Subjects
        Female
    		 81 169 250
        Male
    		 108 236 344
    WHO classification for COVID-19 at the time of screening
    Units: Subjects
        Moderate pneumonia
    		 27 82 109
        Severe pneumonia
    		 162 323 485
    WHO classification for COVID-19 before start of the study drug
    Units: Subjects
        Moderate pneumonia
    		 12 39 51
        Severe pneumonia
    		 177 366 543
    Comorbidities
    Units: Subjects
        Type 2 diabetes mellitus
    		 28 66 94
        Chronic heart failure
    		 5 13 18
        Chronic renal disease
    		 1 9 10
        Chronic obstructive pulmonary disease
    		 9 15 24
        Coronary heart disease
    		 13 28 41
        Atrial fibrillation
    		 8 20 28
        Depression
    		 9 25 34
        None
    		 116 229 345
    Use of oxygen at screening
    Disposition of the use of oxygen at screening
    Units: Subjects
        Moderate patients hospitalized without oxygen
    		 27 82 109
        Severe patients hospitalized in need of oxygen
    		 162 323 485
    Use of oxygen at randomization
    Disposition of the use of oxygen at randomization
    Units: Subjects
        Patients hospitalized without oxygen
    		 12 39 51
        Patients hospitalized with oxygen
    		 177 366 543
    Co-administered Remdesivir
    Units: Subjects
        Yes
    		 141 298 439
        No
    		 48 107 155
    Co-administered Dexamethasone at enrollment
    Units: Subjects
        Yes
    		 160 326 486
        No
    		 29 79 108
    Co-administered Dexamethasone over follow-up due to progression from moderate to severe disease
    Units: Subjects
        Yes
    		 8 16 24
        No
    		 181 389 570
    Co-administered low molecular weight heparin
    Units: Subjects
        Yes
    		 175 385 560
        No
    		 14 20 34
    Co-administered β-lactamase inhibitors
    Units: Subjects
        Yes
    		 10 23 33
        No
    		 179 382 561
    Co-administered Piperacillin/tazobactam
    Units: Subjects
        Yes
    		 36 64 100
        No
    		 153 341 494
    Co-administered Ceftriaxone
    Units: Subjects
        Yes
    		 85 155 240
        No
    		 104 250 354
    Co-administered Ceftaroline
    Units: Subjects
        Yes
    		 32 75 107
        No
    		 157 330 487
    Co-administered respiratory fluoroquinolone
    Units: Subjects
        Yes
    		 24 53 77
        No
    		 165 352 517
    Co-administered Azithromycin
    Units: Subjects
        Yes
    		 35 76 111
        No
    		 154 329 483
    Co-administered any glycopeptide
    Units: Subjects
        Yes
    		 19 24 43
        No
    		 170 381 551
    Co-administered linezolid
    Units: Subjects
        Yes
    		 22 45 67
        No
    		 167 360 527
    Body mass index
    Mean body mass index (BMI) was 29.5 for the FAS.
    Units: Number
        arithmetic mean (standard deviation)
    		 29.8 ( 5.6 ) 29.4 ( 5.5 ) -
    Charlson’s comorbidity index
    Units: Number
        arithmetic mean (standard deviation)
    		 2.2 ( 1.5 ) 2.3 ( 1.6 ) -
    SOFA score
    Sequential Organ Failure Assessment score ranging from 0 to 24
    Units: Number
        arithmetic mean (standard deviation)
    		 2.5 ( 1.2 ) 2.4 ( 1.1 ) -
    Days to start of study drug from symptom onset
    Units: Number
        median (inter-quartile range (Q1-Q3))
    		 9 (7 to 11) 9 (7 to 12) -
    Days to start of study drug from hospital admission
    Units: Number
        median (inter-quartile range (Q1-Q3))
    		 2 (2 to 3) 2 (2 to 3) -
    White blood cell count
    cells per mm3
    Units: Number
        median (inter-quartile range (Q1-Q3))
    		 5910 (4280 to 8300) 5980 (4320 to 8180) -
    Lymphocyte count
    Cells per mm3
    Units: number
        median (inter-quartile range (Q1-Q3))
    		 730 (560 to 1090) 815 (570 to 1110) -
    C-reactive protein
    mg/litre
    Units: mg/litre
        median (inter-quartile range (Q1-Q3))
    		 51.4 (25.2 to 97.9) 50.5 (25.3 to 100.9) -
    Interleukin-6
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    		 20.1 (7.4 to 44.9) 15.5 (6.6 to 39.3) -
    Ferritin
    Units: ng/mL
        median (inter-quartile range (Q1-Q3))
    		 628.6 (293.5 to 1062.3) 558.9 (294.1 to 1047) -
    Serum soluble uPAR
    Units: ng/mL
        median (inter-quartile range (Q1-Q3))
    		 7.5 (6.9 to 9.3) 7.6 (7 to 9.1) -
    D-dimers
    Units: mg/L
        median (inter-quartile range (Q1-Q3))
    		 0.51 (0.31 to 0.92) 0.52 (0.30 to 1.0) -
    PO2:FiO2
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    		 215 (161 to 293) 235 (178 to 304) -
    Administered doses of study drug
    Units: Number
        arithmetic mean (standard deviation)
    		 8.7 ( 2.0 ) 8.4 ( 2.1 ) -

    End points

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    End points reporting groups
    Reporting group title
    Treatment Arm 1
    Reporting group description
    		 0.67 mL of 0.9% sodium chloride, administered s.c. once daily for 10 days

    Reporting group title
    Treatment Arm 2
    Reporting group description
    		 Anakinra 100 mg (0.67 mL) in a prefilled syringe, administered s.c. once daily for 10 days
    Reporting group title
    Treatment Arm 1
    Reporting group description
    		 0.67 mL of 0.9% sodium chloride, administered s.c. once daily for 10 days

    Reporting group title
    Treatment Arm 2
    Reporting group description
    		 Anakinra 100 mg (0.67 mL) in a prefilled syringe, administered s.c. once daily for 10 days
    Reporting group title
    Treatment Arm 1
    Reporting group description
    		 0.67 mL of 0.9% sodium chloride, administered s.c. once daily for 10 days

    Reporting group title
    Treatment Arm 2
    Reporting group description
    		 Anakinra 100 mg (0.67 mL) in a prefilled syringe, administered s.c. once daily for 10 days
    Reporting group title
    Treatment Arm 1
    Reporting group description
    		 0.67 mL of 0.9% sodium chloride, administered s.c. once daily for 10 days

    Reporting group title
    Treatment Arm 2
    Reporting group description
    		 Anakinra 100 mg (0.67 mL) in a prefilled syringe, administered s.c. once daily for 10 days
    Reporting group title
    Treatment Arm 1
    Reporting group description
    		 0.67 mL of 0.9% sodium chloride, administered s.c. once daily for 10 days

    Reporting group title
    Treatment Arm 2
    Reporting group description
    		 Anakinra 100 mg (0.67 mL) in a prefilled syringe, administered s.c. once daily for 10 days
    Reporting group title
    Treatment Arm 1
    Reporting group description
    		 0.67 mL of 0.9% sodium chloride, administered s.c. once daily for 10 days

    Reporting group title
    Treatment Arm 2
    Reporting group description
    		 Anakinra 100 mg (0.67 mL) in a prefilled syringe, administered s.c. once daily for 10 days
    Reporting group title
    Treatment Arm 1
    Reporting group description
    		 0.67 mL of 0.9% sodium chloride, administered s.c. once daily for 10 days

    Reporting group title
    Treatment Arm 2
    Reporting group description
    		 Anakinra 100 mg (0.67 mL) in a prefilled syringe, administered s.c. once daily for 10 days

    Primary: Efficacy of early start of anakinra treatment 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-CPS.

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    End point title
    		 Efficacy of early start of anakinra treatment 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-CPS.
    End point description
    Εfficacy of early start of anakinra treatment 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-CPS.
    End point type
    Primary
    End point timeframe
    28 Days
    End point values
    		 Treatment Arm 1 Treatment Arm 2
    Number of subjects analysed
    189
    405
    Units: Individuals
        Fully recovered PCR (-)
    50
    204
        Asymptomatic PCR (+)
    6
    40
        Symptomatic independent
    74
    93
        Symptomatic assistance needed
    21
    25
        Hospitalized no need for oxygen
    3
    9
        Hospitalized with nasal/mask oxygen
    10
    8
        Need for HFO or NIV
    1
    1
        Mechanical ventilation with P/F >150
    1
    1
        Mechanical ventilation with P/F <150 or vasopre
    4
    5
        Mechanical ventilation with P/F <150 and vasopr
    6
    6
        Dead
    13
    13
    Attachments
    		 Study primary outcome - WHO-CPS at Day 28 - FAS
    Statistical analysis title
    		 Ordinal logistic regression
    Statistical analysis description
    Multivariate ordinal regression was the primary statistical analysis procedure followed. The basic assumption of the model was the assumption of proportional odds (also called the assumption of parallel lines), which was checked by performing the relevant chi-square test and the goodness-of-fit test reported through Pearson’s chi-square test. The dependent variable was the 11-point WHO CPS scale, and the primary independent variable was the arm of treatment.
    Comparison groups
    Treatment Arm 1 v Treatment Arm 2
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 Ordinal logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 0.5
    Notes
    [1] - Null hypothesis testing
    [2] - p value has reached p<0.0001

    Secondary: Supporting analysis of the WHO-CPS at Day 14

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    End point title
    		 Supporting analysis of the WHO-CPS at Day 14
    End point description
    The first supporting analysis of the WHO-CPS at Day 14 is to assess whether anakinra can demonstrate benefit earlier than Day 28.
    End point type
    Secondary
    End point timeframe
    14 days
    End point values
    		 Treatment Arm 1 Treatment Arm 2
    Number of subjects analysed
    189
    405
    Units: Individuals
        Fully recovered PCR (-)
    8
    25
        Asymptomatic PCR (+)
    17
    82
        Symptomatic independent
    70
    139
        Symptomatic assistance needed
    21
    35
        Hospitalized no need for oxygen
    17
    42
        Hospitalized with nasal/mask oxygen
    29
    55
        Need for HFO or NIV
    4
    5
        Mechanical ventilation with P/F >150
    4
    2
        Mechanical ventilation with P/F <150 or vasopre
    8
    11
        Mechanical ventilation with P/F <150 and vasopr
    7
    9
        Dead
    4
    0
    Attachments
    		 WHO-CPS at Day 14 - FAS population
    Statistical analysis title
    		 Ordinal regression
    Statistical analysis description
    The adjusted OR after multivariate analysis was 0.58 (95% CI: 0.42 to 0.79; p<0.001).
    Comparison groups
    Treatment Arm 1 v Treatment Arm 2
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.001
    Method
    		 Ordinal logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 0.79
    Notes
    [3] - Null hypothesis testing

    Secondary: Change of the WHO-CPS at Day 28

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    End point title
    		 Change of the WHO-CPS at Day 28
    End point description
    Ordinal regression analysis showing that anakinra treatment reduced the 11-point WHO-CPS at Day 28 from baseline Day 1 .
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Treatment Arm 1 Treatment Arm 2
    Number of subjects analysed
    189
    405
    Units: points
        median (inter-quartile range (Q1-Q3))
    -3 (-4.5 to -2)
    -4 (-5 to -3)
    Attachments
    		 Absolute change of WHO-CPS at Day 28
    Statistical analysis title
    		 Ordinal logistic regression
    Statistical analysis description
    Covariates entered in the multivariate model were those used for stratified randomization. The ordinal regression analysis showed that anakinra treatment reduced the 11-point WHO-CPS at Day 28 compared to placebo (OR: 0.40; 95% CI: 0.29-0.55; p<0.0001).
    Comparison groups
    Treatment Arm 1 v Treatment Arm 2
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 < 0.0001
    Method
    		 Ordinal logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 0.55
    Notes
    [4] - Null hypothesis testing

    Secondary: Change of the WHO-CPS at Day 14

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    End point title
    		 Change of the WHO-CPS at Day 14
    End point description
    End point type
    Secondary
    End point timeframe
    14 days
    End point values
    		 Treatment Arm 1 Treatment Arm 2
    Number of subjects analysed
    189
    405
    Units: points
        median (inter-quartile range (Q1-Q3))
    -2 (-3 to 0)
    -3 (-3 to -1)
    Attachments
    		 Absolute change of WHO-CPS at Day 14
    Statistical analysis title
    		 Ordinal logistic regression
    Statistical analysis description
    Covariates entered in the multivariate model were those used for stratified randomization. The ordinal regression analysis showed that anakinra treatment reduced the 11-point WHO-CPS at Day 14 compared to placebo (OR: 0.63; 95% CI: 0.46 to 0.86; p=0.003).
    Comparison groups
    Treatment Arm 1 v Treatment Arm 2
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.003 [6]
    Method
    		 Ordinal logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.86
    Notes
    [5] - Null hypothesis testing
    [6] - p=0.003

    Secondary: Change of the sequential organ failure assessment score by Day 14

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    End point title
    		 Change of the sequential organ failure assessment score by Day 14
    End point description
    The ordinal regression analysis showed a non-significant result for absolute change of SOFA score from baseline by Day 14 (OR: 0.67; 95% CI 0.39 to 1.15; p=0.150). Covariates entered in the multivariate model were those used for stratified randomization.
    End point type
    Secondary
    End point timeframe
    14 days
    End point values
    		 Treatment Arm 1 Treatment Arm 2
    Number of subjects analysed
    66
    120
    Units: points
        median (inter-quartile range (Q1-Q3))
    0 (-1 to 2)
    -1 (-2 to 1)
    Attachments
    		 Absolute change of the SOFA score by Day 14
    Statistical analysis title
    		 Ordinal logistic regression
    Statistical analysis description
    The ordinal regression analysis showed a non-significant result for absolute change of SOFA score from baseline by Day 14 (OR: 0.67; 95% CI 0.39 to 1.15; p=0.150). Covariates entered in the multivariate model were those used for stratified randomization.
    Comparison groups
    Treatment Arm 2 v Treatment Arm 1
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.15 [8]
    Method
    		 Ordinal logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 1.15
    Notes
    [7] - Null hypothesis testing
    [8] - p=0.150 (non significant)

    Secondary: Change of the sequential organ failure assessment score by Day 7

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    End point title
    		 Change of the sequential organ failure assessment score by Day 7
    End point description
    The ordinal regression analysis showed that anakinra treatment lead to an absolute reduction of the SOFA score by Day 7 compared to placebo (OR: 0.64; 95% CI: 0.47 to 0.88; p=0.007). Covariates entered in the multivariate model were those used for stratified randomization.
    End point type
    Secondary
    End point timeframe
    7 days
    End point values
    		 Treatment Arm 1 Treatment Arm 2
    Number of subjects analysed
    184
    392
    Units: points
        median (inter-quartile range (Q1-Q3))
    0 (-1 to 0)
    -1 (-2 to 0)
    Attachments
    		 Absolute change of the SOFA score by Day 7
    Statistical analysis title
    		 Ordinal logistic regression
    Statistical analysis description
    The ordinal regression analysis showed that anakinra treatment lead to an absolute reduction of the SOFA score by Day 7 compared to placebo (OR: 0.64; 95% CI: 0.47 to 0.88; p=0.007). Covariates entered in the multivariate model were those used for stratified randomization.
    Comparison groups
    Treatment Arm 1 v Treatment Arm 2
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.007 [10]
    Method
    		 Ordinal logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 0.88
    Notes
    [9] - Null hypothesis testing
    [10] - p=0.007

    Secondary: Time until discharge from hospital

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    End point title
    		 Time until discharge from hospital
    End point description
    A multivariate Cox regression analysis was performed, to determine the difference to live discharge from hospital (days) taking into account the following variables: Intake of Anakinra treatment, Severe COVID-19 by WHO classification, Dexamethasone treatment, BMI >30 kg/m2, Country (Italy/Greece)
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    		 Treatment Arm 1 Treatment Arm 2
    Number of subjects analysed
    179
    388
    Units: days
        median (full range (min-max))
    11 (3 to 90)
    10 (4 to 90)
    Attachments
    		 Cox regression analysis - discharge by day 90
    Statistical analysis title
    		 Cox regression analysis
    Statistical analysis description
    By Day 90, 184 (97.4%) of the 189 patients in the placebo+SoC group and 404 (99.8%) of the 405 patients in the anakinra+SoC group were discharged from the hospital or died (p=0.037) between the 2 arms of treatment by the Fisher exact test). The multivariate Cox regression analysis showed that the time until hospital discharge was 1 day shorter in the anakinra+SoC group than in the placebo+SoC group (HR: 1.26; 95% CI: 0.05 to 1.52; p=0.013).
    Comparison groups
    Treatment Arm 1 v Treatment Arm 2
    Number of subjects included in analysis
    567
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.013 [12]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 1.52
    Notes
    [11] - Null hypothesis testing
    [12] - p=0.013

    Secondary: Time until discharge from the intensive care unit

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    End point title
    		 Time until discharge from the intensive care unit
    End point description
    This analysis included only the patients who were admitted in the ICU. No patients were in the ICU at baseline. Overall, 31 (16.4%) patients in the placebo+SoC group were admitted in the ICU compared to 39 (9.6%) patients in the anakinra+SoC group.
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    		 Treatment Arm 1 Treatment Arm 2
    Number of subjects analysed
    31
    39
    Units: days
        median (full range (min-max))
    15 (1 to 39)
    7.5 (2 to 19)
    Attachments
    		 Time until discharge from the ICU at Day 90
    Statistical analysis title
    		 Cox regression analysis
    Statistical analysis description
    The univariate Cox regression analysis showed that the median time until ICU discharge was 7.5 days shorter in the anakinra+SoC group than in the placebo+SoC group (HR: 2.31; 95% CI: 1.08-4.93; p=0.031). A multivariate analysis was not possible for this endpoint due to the small number of patients.
    Comparison groups
    Treatment Arm 1 v Treatment Arm 2
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.031 [14]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.08
         upper limit
    		 4.93
    Notes
    [13] - Null hypothesis testing
    [14] - p=0.031

    Secondary: WHO-CPS at Day 60

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    End point title
    		 WHO-CPS at Day 60
    End point description
    End point type
    Secondary
    End point timeframe
    60 days
    End point values
    		 Treatment Arm 1 Treatment Arm 2
    Number of subjects analysed
    183
    392
    Units: Individuals
        Fully recovered PCR(-)
    93
    280
        Asymptomatic PCR (+)
    4
    7
        Symptomatic independent
    51
    70
        Symptomatic assistance needed
    9
    10
        Hospitalized no need for oxygen
    1
    1
        Hospitalized with nasal/mask oxygen
    4
    1
        Need for HFO or NIV
    0
    0
        Mechanical ventilation with P/F >150
    1
    0
        Mechanical ventilation with P/F <150 or vasopresso
    1
    0
        Mechanical ventilation with P/F <150 and vasopress
    1
    2
        Dead
    18
    21
    Attachments
    		 WHO-CPS by Day 60
    Statistical analysis title
    		 Ordinal logistic regression
    Statistical analysis description
    Covariates entered in the multivariate model were those used for stratified randomization. The ordinal regression analysis showed that anakinra treatment reduced the odds for higher scores on the 11-point WHO-CPS at Day 60 compared to placebo (OR: 0.40, 95% CI: 0.28-0.58, p<0.0001).
    Comparison groups
    Treatment Arm 1 v Treatment Arm 2
    Number of subjects included in analysis
    575
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 < 0.0001 [16]
    Method
    		 Ordinal logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 0.58
    Notes
    [15] - Null hypothesis testing
    [16] - p<0.0001

    Secondary: WHO-CPS at Day 90

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    End point title
    		 WHO-CPS at Day 90
    End point description
    Covariates entered in the multivariate model were those used for stratified randomization. The ordinal regression analysis showed that anakinra treatment reduced the odds of higher scores on the 11-point WHO-CPS at Day 90 compared to placebo (OR: 0.50, 95% CI: 0.34-0.74, p=0.001).
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    		 Treatment Arm 1 Treatment Arm 2
    Number of subjects analysed
    179
    388
    Units: Individuals
        Fully recovered PCR (-)
    115
    304
        Asymptomatic PCR (+)
    2
    2
        Symptomatic independent
    34
    50
        Symptomatic assistance needed
    4
    8
        Hospitalized no need for oxygen
    3
    1
        Hospitalized with nasal/mask oxygen
    1
    0
        Need for HFO or NIV
    0
    0
        Mechanical ventilation with P/F >150
    1
    1
        Mechanical ventilation with P/F <150 or vasopresso
    0
    0
        Mechanical ventilation with P/F <150 and vasopress
    0
    0
        Dead
    19
    22
    Attachments
    		 WHO-CPS by Day 90
    Statistical analysis title
    		 Ordinal logistic regression
    Statistical analysis description
    Covariates entered in the multivariate model were those used for stratified randomization. The ordinal regression analysis showed that anakinra treatment reduced the odds of higher scores on the 11-point WHO-CPS at Day 90 compared to placebo (OR: 0.50, 95% CI: 0.34-0.74, p=0.001).
    Comparison groups
    Treatment Arm 1 v Treatment Arm 2
    Number of subjects included in analysis
    567
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.001 [18]
    Method
    		 Ordinal logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 0.74
    Notes
    [17] - Null hypothesis testing
    [18] - p=0.001

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    23 December 2020-28 June 2021
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Treatment Arm 1
    Reporting group description
    		 0.67 mL of 0.9% sodium chloride, administered s.c. once daily for 10 days

    Reporting group title
    Treatment Arm 2
    Reporting group description
    		 Anakinra 100 mg (0.67 mL) in a prefilled syringe, administered s.c. once daily for 10 days

    Serious adverse events
    		 Treatment Arm 1 Treatment Arm 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    41 / 189 (21.69%)
    65 / 405 (16.05%)
         number of deaths (all causes)
    17
    18
         number of deaths resulting from adverse events
    17
    18
    Vascular disorders
    Arterial thrombosis
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haematoma muscle
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    4 / 189 (2.12%)
    6 / 405 (1.48%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Surgical and medical procedures
    Hospitalization
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device related infection
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 189 (1.06%)
    2 / 405 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumomediastinum
         subjects affected / exposed
    2 / 189 (1.06%)
    3 / 405 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Pneumothorax
         subjects affected / exposed
    2 / 189 (1.06%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Gamma-glutamyltrasferase increased
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 189 (0.53%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    2 / 189 (1.06%)
    3 / 405 (0.74%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 189 (0.53%)
    3 / 405 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 189 (0.53%)
    2 / 405 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 189 (1.59%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    0 / 189 (0.00%)
    3 / 405 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Mesenteritis
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Subcutaneous emphysema
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 189 (0.53%)
    4 / 405 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bacteremia
         subjects affected / exposed
    5 / 189 (2.65%)
    11 / 405 (2.72%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 11
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    Clostridioides difficile infection
         subjects affected / exposed
    2 / 189 (1.06%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung empyema
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hospital-acquired infection
         subjects affected / exposed
    7 / 189 (3.70%)
    10 / 405 (2.47%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 10
         deaths causally related to treatment / all
    0 / 3
    0 / 4
    Ventilator-associated pneumonia
         subjects affected / exposed
    15 / 189 (7.94%)
    9 / 405 (2.22%)
         occurrences causally related to treatment / all
    2 / 15
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hospital-acquired pneumonia
         subjects affected / exposed
    5 / 189 (2.65%)
    6 / 405 (1.48%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    4 / 189 (2.12%)
    5 / 405 (1.23%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    5 / 189 (2.65%)
    4 / 405 (0.99%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    1 / 189 (0.53%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin and skin structure infection
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    2 / 189 (1.06%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 189 (1.06%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    1 / 189 (0.53%)
    4 / 405 (0.99%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 189 (0.53%)
    2 / 405 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 189 (0.00%)
    2 / 405 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Treatment Arm 1 Treatment Arm 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    156 / 189 (82.54%)
    335 / 405 (82.72%)
    Investigations
    Aminotransferase increase
         subjects affected / exposed
    63 / 189 (33.33%)
    145 / 405 (35.80%)
         occurrences all number
    63
    145
    Amylase increase
         subjects affected / exposed
    13 / 189 (6.88%)
    19 / 405 (4.69%)
         occurrences all number
    13
    19
    Vascular disorders
    Epistaxis
         subjects affected / exposed
    2 / 189 (1.06%)
    10 / 405 (2.47%)
         occurrences all number
    2
    11
    Superficial thrombophlebitis
         subjects affected / exposed
    3 / 189 (1.59%)
    3 / 405 (0.74%)
         occurrences all number
    3
    3
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    19 / 189 (10.05%)
    36 / 405 (8.89%)
         occurrences all number
    20
    36
    Arrythmia
         subjects affected / exposed
    0 / 189 (0.00%)
    1 / 405 (0.25%)
         occurrences all number
    0
    1
    Sinus tachycardia
         subjects affected / exposed
    7 / 189 (3.70%)
    16 / 405 (3.95%)
         occurrences all number
    7
    16
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 189 (4.23%)
    16 / 405 (3.95%)
         occurrences all number
    8
    16
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    5 / 189 (2.65%)
    14 / 405 (3.46%)
         occurrences all number
    5
    14
    Leukocytosis
         subjects affected / exposed
    19 / 189 (10.05%)
    39 / 405 (9.63%)
         occurrences all number
    22
    48
    Neutropenia
         subjects affected / exposed
    1 / 189 (0.53%)
    12 / 405 (2.96%)
         occurrences all number
    1
    13
    Lymphocytopenia
         subjects affected / exposed
    25 / 189 (13.23%)
    40 / 405 (9.88%)
         occurrences all number
    29
    47
    Anemia
         subjects affected / exposed
    37 / 189 (19.58%)
    59 / 405 (14.57%)
         occurrences all number
    39
    61
    Thrombocytopenia
         subjects affected / exposed
    4 / 189 (2.12%)
    9 / 405 (2.22%)
         occurrences all number
    5
    10
    Thrombocytosis
         subjects affected / exposed
    13 / 189 (6.88%)
    24 / 405 (5.93%)
         occurrences all number
    13
    24
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    0 / 189 (0.00%)
    2 / 405 (0.49%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Nausea, Vomiting
         subjects affected / exposed
    1 / 189 (0.53%)
    9 / 405 (2.22%)
         occurrences all number
    1
    9
    Constipation
         subjects affected / exposed
    16 / 189 (8.47%)
    39 / 405 (9.63%)
         occurrences all number
    16
    39
    Diarrhea
         subjects affected / exposed
    8 / 189 (4.23%)
    14 / 405 (3.46%)
         occurrences all number
    8
    14
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 189 (1.59%)
    15 / 405 (3.70%)
         occurrences all number
    3
    15
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    11 / 189 (5.82%)
    33 / 405 (8.15%)
         occurrences all number
    12
    34
    Delirium
         subjects affected / exposed
    2 / 189 (1.06%)
    3 / 405 (0.74%)
         occurrences all number
    2
    3
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    9 / 189 (4.76%)
    17 / 405 (4.20%)
         occurrences all number
    9
    17
    Metabolism and nutrition disorders
    Hyperglycemia
         subjects affected / exposed
    76 / 189 (40.21%)
    148 / 405 (36.54%)
         occurrences all number
    85
    161
    Hypoglycemia
         subjects affected / exposed
    15 / 189 (7.94%)
    34 / 405 (8.40%)
         occurrences all number
    15
    35
    Hyponatremia
         subjects affected / exposed
    23 / 189 (12.17%)
    32 / 405 (7.90%)
         occurrences all number
    23
    33
    Hypernatremia
         subjects affected / exposed
    17 / 189 (8.99%)
    46 / 405 (11.36%)
         occurrences all number
    20
    52
    Hypokalemia
         subjects affected / exposed
    12 / 189 (6.35%)
    11 / 405 (2.72%)
         occurrences all number
    12
    11
    Hyperkalemia
         subjects affected / exposed
    13 / 189 (6.88%)
    36 / 405 (8.89%)
         occurrences all number
    13
    38
    Hypercalcemia
         subjects affected / exposed
    1 / 189 (0.53%)
    4 / 405 (0.99%)
         occurrences all number
    1
    4
    Hypocalcemia
         subjects affected / exposed
    20 / 189 (10.58%)
    32 / 405 (7.90%)
         occurrences all number
    20
    33
    Hypermagnesemia
         subjects affected / exposed
    1 / 189 (0.53%)
    2 / 405 (0.49%)
         occurrences all number
    1
    2
    Hypomagnesemia
         subjects affected / exposed
    1 / 189 (0.53%)
    3 / 405 (0.74%)
         occurrences all number
    1
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34480127
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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