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    Clinical Trial Results:
    A prospective, randomized, factorial design, interventional study to compare the safety and efficacy of combinations of blockade of interleukin-6 pathway and interleukin-1 pathway to best standard of care in improving oxygenation and short- and long-term outcome of COVID-19 patients with acute hypoxic respiratory failure and systemic cytokine release syndrome.

    Summary
    EudraCT number
    		 2020-001500-41
    Trial protocol
    		 BE  
    Global end of trial date
    21 May 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jun 2022
    First version publication date
    04 Jun 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    COV-AID
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04330638
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UZ Gent
    Sponsor organisation address
    C. Heymanslaan 10, Ghent, Belgium, 9000
    Public contact
    HIRUZ CTU, University Hospital Ghent, +32 93320500, hiruz.ctu@uzgent.be
    Scientific contact
    HIRUZ CTU, University Hospital Ghent, +32 93320500, hiruz.ctu@uzgent.be
    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
    10 May 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Dec 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    21 May 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Study if blockade of IL-6 +/- IL-1 to block the cytokine storm and acute lung injury in comparison with usual care reduces time to clinical improvement as defined by an increase of more than 2 on the 6 point ordinal scale or discharge from the hospital
    Protection of trial subjects
    Ethics review and approval, informed consent, supportive care and routine monitoring.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Apr 2020
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 5 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 342
    Worldwide total number of subjects
    342
    EEA total number of subjects
    342
    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)
    167
    From 65 to 84 years
    166
    85 years and over
    9

    Subject disposition

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    Recruitment
    Recruitment details
    		 342 patients were screened in the period from 04-apr-2020 till 06-dec-2020. 342 patients were included, 342 patients were randomised. End of trial notification was dated 21-may-2021 (last patient last visit) and submitted to EC and CA 08-jul-2021.

    Pre-assignment
    Screening details
    		 Confirmed COVID-19 patients between the age of 18 and 80 years were screened for acute hypoxic respiratory failure (saturation <93% on minimal 2 L/min O2 or PaO2/FiO2 <350). Invasive mechanical ventilation >24h, history of severe allergic reactions and unlikely to servive beyond 48h were the most important exclusion criteria.

    Period 1
    Period 1 title
    overall trial
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 A: Usual Care
    Arm description
    		 Usual Care
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 B: Kineret
    Arm description
    		 Kineret® (Anakinra) 100mg pre-filled syringe given 1x / day for 28 days (or until discharge from hospital)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Kineret
    Investigational medicinal product code
    Other name
    Anakinra
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Kineret® (Anakinra) 100mg pre-filled syringe. Will be given 1x / day 100 mg SC 28 days (or until discharge from hospital) Do not shake. Allow the pre-filled syringe to reach room temperature before the injection. Subcutaneous injection; It is recommended that the injection site would be varied to avoid discomfort at the site of injection. Cooling the injection site, prewarming/preheating the injection liquid to reach room temperature, use of cold packs (before and after the injection) and use of topical glucocorticoids and antihistamines after injection may reduce the signs and symptoms of the reaction at the injection site.

    Arm title
    		 C: Sylvant
    Arm description
    		 Sylvant® (Siltuximab) single IV infusion from 100mg powder concentrate and 400mg powder concentrate.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sylvant
    Investigational medicinal product code
    Other name
    Siltuximab
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Sylvant® (Siltuximab) 100mg powder concentrate. Single IV infusion at a dose of 11 mg / kg given over 1 hour as an intravenous infusion in glucose 5% (Ad-preparation: the same volume of product must be withdrawn from the infusion before adding the Sylvant®) Administered via using PVC, or polyurethane (PU), or PE coated administration sets with a 0.2-micron in-line polyethersulfone (PES) filter.

    Investigational medicinal product name
    Sylvant
    Investigational medicinal product code
    Other name
    Siltuximab
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Sylvant® (Siltuximab) 400mg powder concentrate. Single IV infusion at a dose of 11 mg / kg given over 1 hour as an intravenous infusion in glucose 5% (Ad-preparation: the same volume of product must be withdrawn from the infusion before adding the Sylvant®) Administered via using PVC, or polyurethane (PU), or PE coated administration sets with a 0.2-micron in-line polyethersulfone (PES) filter.

    Arm title
    		 D: Kineret + Sylvant
    Arm description
    		 Kineret® (Anakinra) 100mg pre-filled syringe given 1x / day for 28 days (or until discharge from hospital) + Sylvant® (Siltuximab) single IV infusion from 100mg powder concentrate and 400 mg powder concentrate.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Kineret
    Investigational medicinal product code
    Other name
    Anakinra
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Kineret® (Anakinra) 100mg pre-filled syringe. Will be given 1x / day 100 mg SC 28 days (or until discharge from hospital) Do not shake. Allow the pre-filled syringe to reach room temperature before the injection. Subcutaneous injection; It is recommended that the injection site would be varied to avoid discomfort at the site of injection. Cooling the injection site, prewarming/preheating the injection liquid to reach room temperature, use of cold packs (before and after the injection) and use of topical glucocorticoids and antihistamines after injection may reduce the signs and symptoms of the reaction at the injection site.

    Investigational medicinal product name
    Sylvant
    Investigational medicinal product code
    Other name
    Siltuximab
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Sylvant® (Siltuximab) 100mg powder concentrate. Single IV infusion at a dose of 11 mg / kg given over 1 hour as an intravenous infusion in glucose 5% (Ad-preparation: the same volume of product must be withdrawn from the infusion before adding the Sylvant®) Administered via using PVC, or polyurethane (PU), or PE coated administration sets with a 0.2-micron in-line polyethersulfone (PES) filter.

    Investigational medicinal product name
    Sylvant
    Investigational medicinal product code
    Other name
    Siltuximab
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Sylvant® (Siltuximab) 400mg powder concentrate. Single IV infusion at a dose of 11 mg / kg given over 1 hour as an intravenous infusion in glucose 5% (Ad-preparation: the same volume of product must be withdrawn from the infusion before adding the Sylvant®) Administered via using PVC, or polyurethane (PU), or PE coated administration sets with a 0.2-micron in-line polyethersulfone (PES) filter.

    Arm title
    		 E: Roactemra
    Arm description
    		 Roactemra® (tocilizumab) IV- Infusion prepared starting from flasks containing 400mg/20ml stock solution (to dilute for infusion) or from Prefilled syringe 162mg / 0.9ml SC
    Arm type
    		 Experimental

    Investigational medicinal product name
    Roactemra
    Investigational medicinal product code
    Other name
    Tocilizimab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Roactemra® (tocilizumab) IV- Infusion prepared starting from flasks containing 400mg/20ml stock solution (to dilute for infusion). Single IV infusion at a dose of 8 mg/kg with a maximum infusion of 800 mg/injection 8mg / kg (= 0.4ml / kg) in an infusion of 100ml NaCl 0.9% and administration over 1 hour. No further specifications regarding the use of a 0.2 or 0.22 filter when administered.

    Investigational medicinal product name
    Roactemra
    Investigational medicinal product code
    Other name
    Tocilizimab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Roactemra® (tocilizumab) IV infusion prepared from Prefilled syringe 162mg / 0.9ml SC. Single IV infusion at a dose of 8 mg/kg with a maximum infusion of 800 mg/injection 8mg / kg (= 0.4ml / kg) in an infusion of 100ml NaCl 0.9% and administration over 1 hour. Use a PO, PE, PP, PBD or PUR infusion line with 0.2 or 0.22 μm PES or PS filter during administation. As a measure of precaution, an inline filter is mandatory.

    Arm title
    		 F: Kineret + Roactemra
    Arm description
    		 Kineret® (Anakinra) 100mg pre-filled syringe given 1x / day for 28 days (or until discharge from hospital) + Roactemra® (tocilizumab) IV- Infusion prepared starting from flasks containing 400mg/20ml stock solution (to dilute for infusion) or from Prefilled syringe 162mg / 0.9ml SC
    Arm type
    		 Experimental

    Investigational medicinal product name
    Kineret
    Investigational medicinal product code
    Other name
    Anakinra
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Kineret® (Anakinra) 100mg pre-filled syringe. Will be given 1x / day 100 mg SC 28 days (or until discharge from hospital) Do not shake. Allow the pre-filled syringe to reach room temperature before the injection. Subcutaneous injection; It is recommended that the injection site would be varied to avoid discomfort at the site of injection. Cooling the injection site, prewarming/preheating the injection liquid to reach room temperature, use of cold packs (before and after the injection) and use of topical glucocorticoids and antihistamines after injection may reduce the signs and symptoms of the reaction at the injection site.

    Investigational medicinal product name
    Roactemra
    Investigational medicinal product code
    Other name
    Tocilizimab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Roactemra® (tocilizumab) IV- Infusion prepared starting from flasks containing 400mg/20ml stock solution (to dilute for infusion). single IV infusion at a dose of 8 mg/kg with a maximum infusion of 800 mg/injection 8mg / kg (= 0.4ml / kg) in an infusion of 100ml NaCl 0.9% and administration over 1 hour. No further specifications regarding the use of a 0.2 or 0.22 filter when administered.

    Investigational medicinal product name
    Roactemra
    Investigational medicinal product code
    Other name
    Tocilizimab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Roactemra® (tocilizumab) IV infusion prepared from Prefilled syringe 162mg / 0.9ml SC. Single IV infusion at a dose of 8 mg/kg with a maximum infusion of 800 mg/injection 8mg / kg (= 0.4ml / kg) in an infusion of 100ml NaCl 0.9% and administration over 1 hour. Use a PO, PE, PP, PBD or PUR infusion line with 0.2 or 0.22 μm PES or PS filter during administation. As a measure of precaution, an inline filter is mandatory.

    Number of subjects in period 1
    		A: Usual Care B: Kineret C: Sylvant D: Kineret + Sylvant E: Roactemra F: Kineret + Roactemra
    Started
    74
    44
    75
    36
    81
    32
    Completed
    56
    30
    52
    27
    65
    25
    Not completed
    18
    14
    23
    9
    16
    7
         Adverse event, serious fatal
    9
    10
    15
    6
    10
    5
         Consent withdrawn by subject
    4
    -
    -
    -
    -
    -
         unknown
    2
    2
    5
    1
    3
    2
         Lost to follow-up
    3
    2
    3
    2
    3
    -
    Period 2
    Period 2 title
    First 28 days
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 No IL-1 blockade
    Arm description
    		 Some patients received IL-6 blockade with Sylvant® (Siltuximab) single IV infusion from 100mg powder concentrate and 400mg powder concentrate, OR Roactemra® (tocilizumab) IV- Infusion prepared starting from flasks containing 400mg/20ml stock solution (to dilute for infusion) or from Prefilled syringe 162mg / 0.9ml SC
    Arm type
    		 Control group in the factorial design

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 IL-1 blockade
    Arm description
    		 All patients received Kineret® (Anakinra) 100mg pre-filled syringe given 1x / day for 28 days (or until discharge from hospital). Some patients also received Sylvant® (Siltuximab) single IV infusion from 100mg powder concentrate and 400mg powder concentrate, OR Roactemra® (tocilizumab) IV- Infusion prepared starting from flasks containing 400mg/20ml stock solution (to dilute for infusion) or from Prefilled syringe 162mg / 0.9ml SC
    Arm type
    		 Experimental

    Investigational medicinal product name
    Kineret
    Investigational medicinal product code
    Other name
    Anakinra
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Kineret® (Anakinra) 100mg pre-filled syringe. Will be given 1x / day 100 mg SC 28 days (or until discharge from hospital) Do not shake. Allow the pre-filled syringe to reach room temperature before the injection. Subcutaneous injection; It is recommended that the injection site would be varied to avoid discomfort at the site of injection. Cooling the injection site, prewarming/preheating the injection liquid to reach room temperature, use of cold packs (before and after the injection) and use of topical glucocorticoids and antihistamines after injection may reduce the signs and symptoms of the reaction at the injection site.

    Arm title
    		 No IL-6 blockade
    Arm description
    		 Some patients received Kineret® (Anakinra) 100mg pre-filled syringe given 1x / day for 28 days (or until discharge from hospital)
    Arm type
    		 Control group in the factorial design

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 IL-6 blockade
    Arm description
    		 Patients received either Sylvant® (Siltuximab) single IV infusion from 100mg powder concentrate and 400mg powder concentrate, OR Roactemra® (tocilizumab) IV- Infusion prepared starting from flasks containing 400mg/20ml stock solution (to dilute for infusion) or from Prefilled syringe 162mg / 0.9ml SC Some patients also received Kineret® (Anakinra) 100mg pre-filled syringe given 1x / day for 28 days (or until discharge from hospital)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Roactemra
    Investigational medicinal product code
    Other name
    Tocilizimab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Roactemra® (tocilizumab) IV- Infusion prepared starting from flasks containing 400mg/20ml stock solution (to dilute for infusion). Single IV infusion at a dose of 8 mg/kg with a maximum infusion of 800 mg/injection 8mg / kg (= 0.4ml / kg) in an infusion of 100ml NaCl 0.9% and administration over 1 hour. No further specifications regarding the use of a 0.2 or 0.22 filter when administered.

    Investigational medicinal product name
    Sylvant
    Investigational medicinal product code
    Other name
    Siltuximab
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Sylvant® (Siltuximab) 100mg powder concentrate. Single IV infusion at a dose of 11 mg / kg given over 1 hour as an intravenous infusion in glucose 5% (Ad-preparation: the same volume of product must be withdrawn from the infusion before adding the Sylvant®) Administered via using PVC, or polyurethane (PU), or PE coated administration sets with a 0.2-micron in-line polyethersulfone (PES) filter.

    Number of subjects in period 2
    		No IL-1 blockade IL-1 blockade No IL-6 blockade IL-6 blockade
    Started
    230
    112
    115
    227
    Completed
    200
    95
    99
    196
    Not completed
    30
    17
    16
    31
         Adverse event, serious fatal
    26
    17
    14
    29
         Consent withdrawn by subject
    4
    -
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 342 342
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 65 (54 to 73) -
    Gender categorical
    Units: Subjects
        Female
    		 77 77
        Male
    		 265 265
    Ordinal scale
    6-point ordinal scale: 1 death, 2 on invasive mechanical ventilation or ECMO, 3 on non-invasive ventilation or high flow oxygen devices, 4 hospitalized, requiring supplemental oxygenn, 5 hospitalized, not requiring supplemental oxygen, 6 not hospitalized
    Units: Subjects
        2.
    		 39 39
        3.
    		 128 128
        4.
    		 169 169
        5.
    		 6 6
    Ethnicity
    Units: Subjects
        White
    		 278 278
        Middle Eastern-Arabian
    		 40 40
        Black
    		 9 9
        Asian
    		 7 7
        Other
    		 8 8
    Glucocorticoids at day of randomisation
    Units: Subjects
        Yes
    		 213 213
        No
    		 129 129
    SOFA score
    Severity of organ failure assessment
    Units: N/A
        median (inter-quartile range (Q1-Q3))
    		 3 (2 to 4) -
    PaO2/FiO2 ratio at baseline
    The ratio of the partial pressure of oxygen (PaO2) to the fraction of inspired oxygen (FiO2; PaO2/FiO2)
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    		 150 (90 to 248) -

    End points

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    End points reporting groups
    Reporting group title
    A: Usual Care
    Reporting group description
    		 Usual Care

    Reporting group title
    B: Kineret
    Reporting group description
    		 Kineret® (Anakinra) 100mg pre-filled syringe given 1x / day for 28 days (or until discharge from hospital)

    Reporting group title
    C: Sylvant
    Reporting group description
    		 Sylvant® (Siltuximab) single IV infusion from 100mg powder concentrate and 400mg powder concentrate.

    Reporting group title
    D: Kineret + Sylvant
    Reporting group description
    		 Kineret® (Anakinra) 100mg pre-filled syringe given 1x / day for 28 days (or until discharge from hospital) + Sylvant® (Siltuximab) single IV infusion from 100mg powder concentrate and 400 mg powder concentrate.

    Reporting group title
    E: Roactemra
    Reporting group description
    		 Roactemra® (tocilizumab) IV- Infusion prepared starting from flasks containing 400mg/20ml stock solution (to dilute for infusion) or from Prefilled syringe 162mg / 0.9ml SC

    Reporting group title
    F: Kineret + Roactemra
    Reporting group description
    		 Kineret® (Anakinra) 100mg pre-filled syringe given 1x / day for 28 days (or until discharge from hospital) + Roactemra® (tocilizumab) IV- Infusion prepared starting from flasks containing 400mg/20ml stock solution (to dilute for infusion) or from Prefilled syringe 162mg / 0.9ml SC
    Reporting group title
    No IL-1 blockade
    Reporting group description
    		 Some patients received IL-6 blockade with Sylvant® (Siltuximab) single IV infusion from 100mg powder concentrate and 400mg powder concentrate, OR Roactemra® (tocilizumab) IV- Infusion prepared starting from flasks containing 400mg/20ml stock solution (to dilute for infusion) or from Prefilled syringe 162mg / 0.9ml SC

    Reporting group title
    IL-1 blockade
    Reporting group description
    		 All patients received Kineret® (Anakinra) 100mg pre-filled syringe given 1x / day for 28 days (or until discharge from hospital). Some patients also received Sylvant® (Siltuximab) single IV infusion from 100mg powder concentrate and 400mg powder concentrate, OR Roactemra® (tocilizumab) IV- Infusion prepared starting from flasks containing 400mg/20ml stock solution (to dilute for infusion) or from Prefilled syringe 162mg / 0.9ml SC

    Reporting group title
    No IL-6 blockade
    Reporting group description
    		 Some patients received Kineret® (Anakinra) 100mg pre-filled syringe given 1x / day for 28 days (or until discharge from hospital)

    Reporting group title
    IL-6 blockade
    Reporting group description
    		 Patients received either Sylvant® (Siltuximab) single IV infusion from 100mg powder concentrate and 400mg powder concentrate, OR Roactemra® (tocilizumab) IV- Infusion prepared starting from flasks containing 400mg/20ml stock solution (to dilute for infusion) or from Prefilled syringe 162mg / 0.9ml SC Some patients also received Kineret® (Anakinra) 100mg pre-filled syringe given 1x / day for 28 days (or until discharge from hospital)

    Primary: Time to clinical improvement

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    End point title
    		 Time to clinical improvement
    End point description
    Median time to clinical improvement
    End point type
    Primary
    End point timeframe
    First 28 days
    End point values
    		 No IL-1 blockade IL-1 blockade No IL-6 blockade IL-6 blockade
    Number of subjects analysed
    230
    112
    115
    227
    Units: days
    12
    12
    12
    11
    Statistical analysis title
    		 Kaplan-Meier estimates for IL-1 blockade
    Statistical analysis description
    Kaplan-Meier estimates of the cumulative incidence function for clinical improvement with pointwise 95% confidence intervals according to the allocated treatment for the first randomization (IL-1 blockade vs. no IL-1 blockade).
    Comparison groups
    No IL-1 blockade v IL-1 blockade
    Number of subjects included in analysis
    342
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.21
    Statistical analysis title
    		 Kaplan-Meier estimates for IL-6 blockade
    Statistical analysis description
    Kaplan-Meier estimates of the cumulative incidence function for clinical improvement with pointwise 95% confidence intervals according to the allocated treatment for the second randomization (IL-6 blockade vs. no IL-6 blockade).
    Comparison groups
    No IL-6 blockade v IL-6 blockade
    Number of subjects included in analysis
    342
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.003
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.29

    Primary: Efficacy endpoint for IL-6 blockade

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    End point title
    		 Efficacy endpoint for IL-6 blockade
    End point description
    Median time to clinical improvement. Clinical improvement was defined as an increase of 2 points on the 6-point ordinal scale or discharge.
    End point type
    Primary
    End point timeframe
    First 28 days
    End point values
    		 No IL-6 blockade IL-6 blockade
    Number of subjects analysed
    115
    227
    Units: days
    12
    11
    Statistical analysis title
    		 Estimated probability of clinical improvement
    Statistical analysis description
    Estimated probability of having experienced clinical improvement at day 28.
    Comparison groups
    No IL-6 blockade v IL-6 blockade
    Number of subjects included in analysis
    342
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.003
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.29

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    screening until follow-up
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    5.0
    Reporting groups
    Reporting group title
    A: Usual Care
    Reporting group description
    		 -

    Reporting group title
    B: Kineret
    Reporting group description
    		 -

    Reporting group title
    C: Sylvant
    Reporting group description
    		 -

    Reporting group title
    D: Kineret + Sylvant
    Reporting group description
    		 -

    Reporting group title
    E: Roactemra
    Reporting group description
    		 -

    Reporting group title
    F: Kineret + Roactemra
    Reporting group description
    		 -

    Serious adverse events
    		 A: Usual Care B: Kineret C: Sylvant D: Kineret + Sylvant E: Roactemra F: Kineret + Roactemra
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 74 (18.92%)
    12 / 44 (27.27%)
    21 / 75 (28.00%)
    8 / 36 (22.22%)
    15 / 81 (18.52%)
    9 / 32 (28.13%)
         number of deaths (all causes)
    9
    10
    15
    6
    10
    5
         number of deaths resulting from adverse events
    Vascular disorders
    Arterial thromboembolism
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    0 / 75 (0.00%)
    1 / 36 (2.78%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thromboembolic event
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 44 (2.27%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Other
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    1 / 81 (1.23%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    1 / 75 (1.33%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    3 / 74 (4.05%)
    2 / 44 (4.55%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    2 / 81 (2.47%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    Immune system disorders
    Anaphylaxis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    0 / 75 (0.00%)
    1 / 36 (2.78%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 74 (2.70%)
    1 / 44 (2.27%)
    2 / 75 (2.67%)
    1 / 36 (2.78%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    1 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    1 / 2
    0 / 1
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    1 / 75 (1.33%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnea
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 44 (0.00%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    0 / 75 (0.00%)
    1 / 36 (2.78%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Laryngeal stenosis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 44 (0.00%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    2 / 75 (2.67%)
    0 / 36 (0.00%)
    1 / 81 (1.23%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 74 (2.70%)
    5 / 44 (11.36%)
    9 / 75 (12.00%)
    2 / 36 (5.56%)
    6 / 81 (7.41%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 9
    2 / 2
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 5
    0 / 7
    2 / 2
    0 / 5
    0 / 1
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    1 / 81 (1.23%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    postoperative haemorrhage
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    1 / 81 (1.23%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Asystole
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    1 / 75 (1.33%)
    0 / 36 (0.00%)
    1 / 81 (1.23%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 44 (2.27%)
    1 / 75 (1.33%)
    0 / 36 (0.00%)
    1 / 81 (1.23%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Other
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    1 / 75 (1.33%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral valve disease
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 44 (0.00%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Edema cerebral
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 44 (0.00%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 44 (0.00%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial haemorrhage
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 44 (2.27%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stroke
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    1 / 75 (1.33%)
    0 / 36 (0.00%)
    1 / 81 (1.23%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Blood and lymphatic system disorders
    Other
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 44 (2.27%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric haemorrhage
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 44 (2.27%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jejunal haemorrhage
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 44 (0.00%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 44 (2.27%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 44 (2.27%)
    1 / 75 (1.33%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 44 (0.00%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Hepatic infection
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 44 (0.00%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 44 (2.27%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    2 / 32 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    3 / 74 (4.05%)
    5 / 44 (11.36%)
    6 / 75 (8.00%)
    3 / 36 (8.33%)
    2 / 81 (2.47%)
    2 / 32 (6.25%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 5
    4 / 6
    3 / 3
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    1 / 3
    2 / 2
    1 / 2
    1 / 1
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    0 / 75 (0.00%)
    1 / 36 (2.78%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 A: Usual Care B: Kineret C: Sylvant D: Kineret + Sylvant E: Roactemra F: Kineret + Roactemra
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 74 (50.00%)
    25 / 44 (56.82%)
    45 / 75 (60.00%)
    17 / 36 (47.22%)
    35 / 81 (43.21%)
    17 / 32 (53.13%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 74 (4.05%)
    3 / 44 (6.82%)
    7 / 75 (9.33%)
    3 / 36 (8.33%)
    7 / 81 (8.64%)
    1 / 32 (3.13%)
         occurrences all number
    4
    3
    10
    3
    11
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 74 (4.05%)
    2 / 44 (4.55%)
    5 / 75 (6.67%)
    2 / 36 (5.56%)
    5 / 81 (6.17%)
    0 / 32 (0.00%)
         occurrences all number
    6
    2
    8
    2
    7
    0
    creatinine increased
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 44 (0.00%)
    1 / 75 (1.33%)
    2 / 36 (5.56%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    1
    2
    0
    0
    GGT inncreased
         subjects affected / exposed
    2 / 74 (2.70%)
    2 / 44 (4.55%)
    5 / 75 (6.67%)
    0 / 36 (0.00%)
    2 / 81 (2.47%)
    0 / 32 (0.00%)
         occurrences all number
    4
    3
    6
    0
    4
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    0 / 75 (0.00%)
    0 / 36 (0.00%)
    1 / 81 (1.23%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    Platelet count decreased
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    4 / 75 (5.33%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    12
    0
    0
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 74 (5.41%)
    3 / 44 (6.82%)
    4 / 75 (5.33%)
    1 / 36 (2.78%)
    3 / 81 (3.70%)
    3 / 32 (9.38%)
         occurrences all number
    4
    3
    4
    1
    3
    3
    Hypotension
         subjects affected / exposed
    4 / 74 (5.41%)
    3 / 44 (6.82%)
    1 / 75 (1.33%)
    0 / 36 (0.00%)
    1 / 81 (1.23%)
    1 / 32 (3.13%)
         occurrences all number
    4
    3
    1
    0
    1
    1
    Thromboembolic event
         subjects affected / exposed
    1 / 74 (1.35%)
    3 / 44 (6.82%)
    4 / 75 (5.33%)
    0 / 36 (0.00%)
    3 / 81 (3.70%)
    0 / 32 (0.00%)
         occurrences all number
    1
    3
    5
    0
    6
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 74 (4.05%)
    0 / 44 (0.00%)
    7 / 75 (9.33%)
    1 / 36 (2.78%)
    0 / 81 (0.00%)
    3 / 32 (9.38%)
         occurrences all number
    3
    0
    7
    1
    0
    3
    Sinus bradycardia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 44 (0.00%)
    8 / 75 (10.67%)
    2 / 36 (5.56%)
    2 / 81 (2.47%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    8
    2
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 74 (4.05%)
    3 / 44 (6.82%)
    4 / 75 (5.33%)
    3 / 36 (8.33%)
    2 / 81 (2.47%)
    0 / 32 (0.00%)
         occurrences all number
    3
    3
    8
    3
    2
    0
    Other
         subjects affected / exposed
    0 / 74 (0.00%)
    3 / 44 (6.82%)
    4 / 75 (5.33%)
    4 / 36 (11.11%)
    3 / 81 (3.70%)
    0 / 32 (0.00%)
         occurrences all number
    0
    3
    5
    4
    3
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    10 / 74 (13.51%)
    5 / 44 (11.36%)
    9 / 75 (12.00%)
    4 / 36 (11.11%)
    8 / 81 (9.88%)
    7 / 32 (21.88%)
         occurrences all number
    11
    5
    10
    4
    8
    7
    Diarrhoea
         subjects affected / exposed
    2 / 74 (2.70%)
    3 / 44 (6.82%)
    3 / 75 (4.00%)
    1 / 36 (2.78%)
    2 / 81 (2.47%)
    1 / 32 (3.13%)
         occurrences all number
    3
    4
    3
    1
    2
    1
    gastroparesis
         subjects affected / exposed
    3 / 74 (4.05%)
    3 / 44 (6.82%)
    1 / 75 (1.33%)
    0 / 36 (0.00%)
    3 / 81 (3.70%)
    1 / 32 (3.13%)
         occurrences all number
    3
    3
    1
    0
    3
    1
    Nausea
         subjects affected / exposed
    4 / 74 (5.41%)
    0 / 44 (0.00%)
    2 / 75 (2.67%)
    2 / 36 (5.56%)
    0 / 81 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    4
    0
    3
    2
    0
    2
    Vomiting
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 44 (2.27%)
    1 / 75 (1.33%)
    2 / 36 (5.56%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    1
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    cough
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 44 (2.27%)
    0 / 75 (0.00%)
    1 / 36 (2.78%)
    1 / 81 (1.23%)
    2 / 32 (6.25%)
         occurrences all number
    1
    1
    0
    1
    1
    2
    Other
         subjects affected / exposed
    0 / 74 (0.00%)
    5 / 44 (11.36%)
    2 / 75 (2.67%)
    0 / 36 (0.00%)
    1 / 81 (1.23%)
    0 / 32 (0.00%)
         occurrences all number
    0
    6
    2
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    1 / 75 (1.33%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    3 / 74 (4.05%)
    2 / 44 (4.55%)
    4 / 75 (5.33%)
    0 / 36 (0.00%)
    2 / 81 (2.47%)
    1 / 32 (3.13%)
         occurrences all number
    3
    2
    4
    0
    2
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 74 (2.70%)
    3 / 44 (6.82%)
    2 / 75 (2.67%)
    0 / 36 (0.00%)
    1 / 81 (1.23%)
    0 / 32 (0.00%)
         occurrences all number
    2
    3
    2
    0
    1
    0
    other
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    1 / 75 (1.33%)
    2 / 36 (5.56%)
    1 / 81 (1.23%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    1
    2
    1
    0
    Musculoskeletal and connective tissue disorders
    Soft tissue necrosis
    Additional description: lower limb
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    0 / 75 (0.00%)
    2 / 36 (5.56%)
    0 / 81 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    2 / 74 (2.70%)
    2 / 44 (4.55%)
    2 / 75 (2.67%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    2
    2
    3
    0
    0
    2
    lung infection
         subjects affected / exposed
    7 / 74 (9.46%)
    4 / 44 (9.09%)
    8 / 75 (10.67%)
    3 / 36 (8.33%)
    8 / 81 (9.88%)
    5 / 32 (15.63%)
         occurrences all number
    13
    5
    17
    5
    10
    7
    Sepsis
         subjects affected / exposed
    3 / 74 (4.05%)
    0 / 44 (0.00%)
    5 / 75 (6.67%)
    0 / 36 (0.00%)
    2 / 81 (2.47%)
    0 / 32 (0.00%)
         occurrences all number
    3
    0
    5
    0
    2
    0
    Urinary tract infection
         subjects affected / exposed
    4 / 74 (5.41%)
    1 / 44 (2.27%)
    1 / 75 (1.33%)
    0 / 36 (0.00%)
    0 / 81 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    4
    1
    1
    0
    0
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 44 (0.00%)
    4 / 75 (5.33%)
    1 / 36 (2.78%)
    2 / 81 (2.47%)
    3 / 32 (9.38%)
         occurrences all number
    2
    0
    4
    1
    2
    3
    Hyperkalaemia
         subjects affected / exposed
    0 / 74 (0.00%)
    2 / 44 (4.55%)
    4 / 75 (5.33%)
    0 / 36 (0.00%)
    3 / 81 (3.70%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    4
    0
    3
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 74 (1.35%)
    2 / 44 (4.55%)
    3 / 75 (4.00%)
    2 / 36 (5.56%)
    1 / 81 (1.23%)
    3 / 32 (9.38%)
         occurrences all number
    1
    2
    3
    2
    1
    3
    Hypokalaemia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 44 (0.00%)
    4 / 75 (5.33%)
    1 / 36 (2.78%)
    0 / 81 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    4
    1
    0
    1
    other
         subjects affected / exposed
    2 / 74 (2.70%)
    1 / 44 (2.27%)
    5 / 75 (6.67%)
    1 / 36 (2.78%)
    0 / 81 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    3
    1
    5
    1
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Apr 2020
    Section 5.1 : Recent (≤14 days of) of flu-like symptoms or malaise prior to randomization) infection with COVID-19 -> changed to ≤16 days section 5.2 : frailty score. exclusion criteria: clinical frailty score >2 -> changed to clinical frailty score > 3 Section 5.1 , inclusion criteria: clinical frailty score deleted section 5.1 : COVID-19 diagnosis: serology and emerging technologies added as diagnostic test Section 5.1 : COVID-19 diagnosis Probable COVID-19 infection defined by chest CT-scan and clinical criteria added
    09 Apr 2020
    Addition Jessa Hospital Hasselt
    21 Apr 2020
    Addition of o CHR de la Citadelle o CHU Tivoli o Cliniques Saint-Pierre Ottignies o AZ Delta o AZ Sint-Lucas Gent o ZNA Section 5.1 : IC1 Confident COVID diagnosis … Section 5.1: IC 4 clarification FiO2 Section 5.1: added extra IC Female subject need to use adequate contraception during treatment and 3 months after treatment Section 7.1.3 : Roactemra sc to IV clarification Section 8.4 : schematic overview Procalcitonin explicit added in overview Section 12.6 data safety monitoring board will be foreseen Section 7.1.3 Dose justification added
    18 Jun 2020
    Section 3.2: ARDS definition changed to “adjusted Berlin criteria”. Section 5.1: typo corrected Section 5.2: Clarification Frailty score added: clinical frailty scale above 3 (This frailty score is the patient status before first symptoms of COVID-19 episode.) Section 5.2: Exclusion criteria added: Patient on ECMO at time of screening Section 7.1.4: Dose adjustment permitted for KINERET if kidney function falls below 30ml/min GFR. Dosing to be adjusted to 100 mg once every other day (q2d) Section 8.4: lay-out of flowchart simplified. Assessments removed: - Clinical Sign Score and NEWS2 - HScore only at D1 - Daily anamnesis and physical examination not requested anymore, only per standard of care or on clinical grounds. - Arterial Blood Gas only required at D0/1, D6, D15 or discharge whichever comes first - Laboratory assessments: ESR, ureum, troponins, CK removed. Procalcitonine required at least 3x/week. Section 9.3: 1500 RPM or 410 g adjusted to -> 1770g Section 12.3: Contact details Marketing Authorisation Holder, SOBI, ROCHE, EUSAPHARMA: removed Section 12.4: Study team informs company that provides IMP was erased
    10 Nov 2020
    Section 8.4: schematic overview error corrected and column “Discharge (only if after D15)” removed. Section 3.2: PEEP > 5 cm H20 on invasive or non-invasive ventilation or flow ≥ 50L/min on HFOT (Optiflow) (Typo “≥ 60L/min” corrected to “≥ 50L/min.) Section 8.2 and section 8.4: If an arterial blood gas value is available of less than 24 hours before randomization, there’s no need to have a new ABG done on Day 0/1. Section 8.4: time window of assessment of vital signs (6-10 AM) is not applicable for the follow-up visit. Section 7.1.4 : In case kidney function falls below 30ml/min GFR, dosing of KINERET® needs to be adjusted to 100mg every other day (q2d). section 7.1.3: Sylvant® (Siltuximab) 100mg powder concentrate added Section 2: Secondary objectives are refined Section 3: Secondary endpoints are refined into sensitivity endpoints for the primary endpoints, secondary endpoints and related sensitivity endpoints, exploratory endpoints, descriptive endpoints and safety endpoints. The description of the endpoints was clarified without substantive changes. Section 10.1 on the sample size calculation Section 10.2 on type of statistical methods clarifies Cox Proportional Hazards models will be stratified according to the other randomization and according to dexamethasone use (as usual care in the treatment of covid19 has changed). Models will not be stratified for centre. Section 10.2 on type of statistical methods Section 2.4 on the primary objective Section 2.6 on exploratory objectives Section 3 on endpoints Section 4.2.1 on the end of study duration for an individual subject Section 3.2: A new sensitivity endpoint related to the primary endpoint has been added Section 4.2 on end of study definition Section 10.1 on sample size calculation Section 3.3 on secondary endpoints Section 10.2 on type of statistical methods Section 3.6 on safety endpoints

    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/34756178
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