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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of Tocilizumab in Patients with Severe COVID-19 Pneumonia

    Summary
    EudraCT number
    2020-001154-22
    Trial protocol
    DK   DE   FR   NL   GB   IT   ES  
    Global end of trial date
    28 Jul 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Jul 2021
    First version publication date
    14 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    WA42380
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04320615
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Hoffmann-La Roche
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, 4070
    Public contact
    F Hoffmann-La Roche AG, Hoffmann-La Roche, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F Hoffmann-La Roche AG, Hoffmann-La Roche, +41 616878333, global.trial_information@roche.com
    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
    22 Sep 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was a randomized, double-blind, placebo-controlled study to assess the efficacy and safety of tocilizumab in combination with standard of care (SOC) compared with matching placebo in combination with SOC in hospitalized adult participants with severe COVID-19 pneumonia.
    Protection of trial subjects
    All participants were required to sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    03 Apr 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 15
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Denmark: 18
    Country: Number of subjects enrolled
    Spain: 31
    Country: Number of subjects enrolled
    France: 27
    Country: Number of subjects enrolled
    United Kingdom: 65
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Netherlands: 13
    Country: Number of subjects enrolled
    United States: 244
    Worldwide total number of subjects
    438
    EEA total number of subjects
    114
    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)
    244
    From 65 to 84 years
    177
    85 years and over
    17

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Inclusion Criteria: - Hospitalized with COVID-19 pneumonia confirmed per WHO criteria (including a positive PCR of any specimen; e.g., respiratory, blood, urine, stool, other bodily fluid) and evidenced by chest X-ray or CT scan - SPO2 </=93% or PaO2/FiO2 <300 mmHg

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo Modified Intent-to-Treat (mITT) Arm
    Arm description
    Participants randomized to the placebo arm who received any amount of study drug. Participants randomized to the placebo arm were to receive 1 IV infusion of placebo matched to TCZ. Up to 1 additional dose could be given if clinical symptoms worsened or showed no improvement.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 IV infusion of placebo matched to TCZ, with up to 1 additional dose if clinical symptoms worsened or showed no improvement.

    Arm title
    Tocilizumab (TCZ) mITT Arm
    Arm description
    Participants randomized to the TCZ arm who received any amount of study drug. Participants randomized to the TCZ arm were to receive 1 intravenous (IV) infusion of TCZ, dosed at 8 mg/kg, up to a maximum dose 800 mg. Up to 1 additional dose could be given if clinical symptoms worsened or showed no improvement.
    Arm type
    Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 intravenous (IV) infusion of TCZ, dosed at 8 mg/kg, up to a maximum dose 800 mg, with up to 1 additional dose if clinical symptoms worsened or showed no improvement.

    Number of subjects in period 1
    Placebo Modified Intent-to-Treat (mITT) Arm Tocilizumab (TCZ) mITT Arm
    Started
    144
    294
    Completed
    96
    190
    Not completed
    48
    104
         Consent withdrawn by subject
    4
    10
         Physician decision
    2
    -
         Death
    35
    71
         Unspecified
    2
    -
         Lost to follow-up
    5
    23

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo Modified Intent-to-Treat (mITT) Arm
    Reporting group description
    Participants randomized to the placebo arm who received any amount of study drug. Participants randomized to the placebo arm were to receive 1 IV infusion of placebo matched to TCZ. Up to 1 additional dose could be given if clinical symptoms worsened or showed no improvement.

    Reporting group title
    Tocilizumab (TCZ) mITT Arm
    Reporting group description
    Participants randomized to the TCZ arm who received any amount of study drug. Participants randomized to the TCZ arm were to receive 1 intravenous (IV) infusion of TCZ, dosed at 8 mg/kg, up to a maximum dose 800 mg. Up to 1 additional dose could be given if clinical symptoms worsened or showed no improvement.

    Reporting group values
    Placebo Modified Intent-to-Treat (mITT) Arm Tocilizumab (TCZ) mITT Arm Total
    Number of subjects
    144 294 438
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    81 163 244
        From 65-84 years
    60 117 177
        85 years and over
    3 14 17
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    60.6 ± 13.7 60.9 ± 14.6 -
    Sex: Female, Male
    Units: Participants
        Female
    43 89 132
        Male
    101 205 306
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    5 8 13
        Asian
    10 28 38
        Native Hawaiian or Other Pacific Islander
    5 3 8
        Black or African American
    26 40 66
        White
    76 176 252
        More than one race
    1 0 1
        Unknown or Not Reported
    21 39 60
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    47 94 141
        Not Hispanic or Latino
    86 181 267
        Unknown or Not Reported
    11 19 30

    End points

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    End points reporting groups
    Reporting group title
    Placebo Modified Intent-to-Treat (mITT) Arm
    Reporting group description
    Participants randomized to the placebo arm who received any amount of study drug. Participants randomized to the placebo arm were to receive 1 IV infusion of placebo matched to TCZ. Up to 1 additional dose could be given if clinical symptoms worsened or showed no improvement.

    Reporting group title
    Tocilizumab (TCZ) mITT Arm
    Reporting group description
    Participants randomized to the TCZ arm who received any amount of study drug. Participants randomized to the TCZ arm were to receive 1 intravenous (IV) infusion of TCZ, dosed at 8 mg/kg, up to a maximum dose 800 mg. Up to 1 additional dose could be given if clinical symptoms worsened or showed no improvement.

    Subject analysis set title
    TCZ - No mechanical ventilation at baseline
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants randomized to the TCZ arm who received any amount of study drug and were not on mechanical ventilation at baseline. Participants randomized to the TCZ arm were to receive 1 intravenous (IV) infusion of TCZ, dosed at 8 mg/kg, up to a maximum dose 800 mg. Up to 1 additional dose could be given if clinical symptoms worsened or showed no improvement.

    Subject analysis set title
    Placebo - No mechanical ventilation at baseline
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants randomized to the placebo arm who received any amount of study drug and were not on mechanical ventilation at baseline. Participants randomized to the placebo arm were to receive 1 IV infusion of placebo matched to TCZ. Up to 1 additional dose could be given if clinical symptoms worsened or showed no improvement.

    Subject analysis set title
    TCZ - Not in ICU at baseline
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants randomized to the TCZ arm who received any amount of study drug and were not in the ICU at baseline. Participants randomized to the TCZ arm were to receive 1 intravenous (IV) infusion of TCZ, dosed at 8 mg/kg, up to a maximum dose 800 mg. Up to 1 additional dose could be given if clinical symptoms worsened or showed no improvement.

    Subject analysis set title
    Placebo - Not in ICU at baseline
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants randomized to the placebo arm who received any amount of study drug and were not in the ICU at baseline. Participants randomized to the placebo arm were to receive 1 IV infusion of placebo matched to TCZ. Up to 1 additional dose could be given if clinical symptoms worsened or showed no improvement.

    Primary: Clinical Status Assessed Using a 7-Category Ordinal Scale at Day 28 (Week 4)

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    End point title
    Clinical Status Assessed Using a 7-Category Ordinal Scale at Day 28 (Week 4)
    End point description
    Clinical status was assessed using a 7-category ordinal scale: 1 - Discharged (or "ready for discharge") 2 - Non- intensive care unit (ICU) hospital ward (or "ready for hospital ward") not requiring supplemental oxygen 3 - Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen 4 - ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen 5 - ICU, requiring intubation and mechanical ventilation 6 - ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support 7 - Death mITT population: Defined as all randomized participants who received any amount of study medication, with participants grouped according to the treatment assigned at randomization.
    End point type
    Primary
    End point timeframe
    Day 28
    End point values
    Placebo Modified Intent-to-Treat (mITT) Arm Tocilizumab (TCZ) mITT Arm
    Number of subjects analysed
    144
    294
    Units: Percentage of Participants
    number (not applicable)
        Category 1
    49.3
    56.5
        Category 2
    5.6
    2.0
        Category 3
    2.8
    4.8
        Category 4
    6.9
    2.0
        Category 5
    9.7
    8.8
        Category 6
    6.3
    6.1
        Category 7
    19.4
    19.7
    Statistical analysis title
    Clinical Status at Day 28 (Week 4)
    Comparison groups
    Placebo Modified Intent-to-Treat (mITT) Arm v Tocilizumab (TCZ) mITT Arm
    Number of subjects included in analysis
    438
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.36
    Method
    Van Elteren Test
    Parameter type
    Median difference (final values)
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.5
         upper limit
    0

    Secondary: Time to Clinical Improvement (TTCI), Defined as a National Early Warning Score 2 (NEWS2) of </= 2 Maintained for 24 Hours

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    End point title
    Time to Clinical Improvement (TTCI), Defined as a National Early Warning Score 2 (NEWS2) of </= 2 Maintained for 24 Hours
    End point description
    Defined as time from first dose of study drug to at least two NEWS2 assessments with a score of <=2 covering a span of at least 21.5 hours, with a maximum of 26.5 hours between the first and last of these assessments and no assessments with a score >2 in between. If one of the components of the NEWS2 score was missing at a particular time point, then the NEWS2 score was not calculated. Participants who died were censored at Day 28. mITT population: Defined as all randomized participants who received any amount of study medication, with participants grouped according to the treatment assigned at randomization. 9999 = Value not estimable (NE) due to an insufficient number of events.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    Placebo Modified Intent-to-Treat (mITT) Arm Tocilizumab (TCZ) mITT Arm
    Number of subjects analysed
    144
    294
    Units: Days
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Statistical analysis title
    Time to Clinical Improvement
    Comparison groups
    Placebo Modified Intent-to-Treat (mITT) Arm v Tocilizumab (TCZ) mITT Arm
    Number of subjects included in analysis
    438
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0443
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.448
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.01
         upper limit
    2.08

    Secondary: Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-Category Ordinal Scale of Clinical Status

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    End point title
    Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-Category Ordinal Scale of Clinical Status
    End point description
    Time to improvement for this outcome measure was defined as the days from the first dose of study drug to when at least a 2-category improvement in clinical status (based on a 7-category ordinal scale) is observed. Participants who died were censored at Day 28. mITT population: Defined as all randomized participants who received any amount of study medication, with participants grouped according to the treatment assigned at randomization.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    Placebo Modified Intent-to-Treat (mITT) Arm Tocilizumab (TCZ) mITT Arm
    Number of subjects analysed
    144
    294
    Units: Days
        median (confidence interval 95%)
    18.0 (15.0 to 28.0)
    14.0 (12.0 to 17.0)
    Statistical analysis title
    Time to improvement on 7-category scale
    Comparison groups
    Placebo Modified Intent-to-Treat (mITT) Arm v Tocilizumab (TCZ) mITT Arm
    Number of subjects included in analysis
    438
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.082
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.263
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.97
         upper limit
    1.64

    Secondary: Time to Hospital Discharge or "Ready for Discharge"

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    End point title
    Time to Hospital Discharge or "Ready for Discharge"
    End point description
    Time to Hospital Discharge was defined as the time from the first dose of study drug to hospital discharge or "ready for discharge" (normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or </=2L supplemental oxygen). Participants who died were censored at Day 28. 9999 = Value not estimable (NE) due to an insufficient number of events. mITT population: Defined as all randomized participants who received any amount of study medication, with participants grouped according to the treatment assigned at randomization.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    Placebo Modified Intent-to-Treat (mITT) Arm Tocilizumab (TCZ) mITT Arm
    Number of subjects analysed
    144
    294
    Units: Days
        median (confidence interval 95%)
    28.0 (20.0 to 9999)
    20.0 (17.0 to 27.0)
    Statistical analysis title
    Time to hospital discharge or ready for discharge
    Comparison groups
    Placebo Modified Intent-to-Treat (mITT) Arm v Tocilizumab (TCZ) mITT Arm
    Number of subjects included in analysis
    438
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.037
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.02
         upper limit
    1.79

    Secondary: Incidence of Mechanical Ventilation by Day 28

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    End point title
    Incidence of Mechanical Ventilation by Day 28
    End point description
    Participants who died by Day 28 were assumed to have required mechanical ventilation. mITT population: Defined as all randomized participants who received any amount of study medication, with participants grouped according to the treatment assigned at randomization.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    Placebo Modified Intent-to-Treat (mITT) Arm Tocilizumab (TCZ) mITT Arm TCZ - No mechanical ventilation at baseline Placebo - No mechanical ventilation at baseline
    Number of subjects analysed
    144
    294
    183
    90
    Units: Percentage of Participants
        number (confidence interval 95%)
    60.4 (52.4 to 68.4)
    54.4 (48.7 to 60.1)
    27.9 (21.4 to 34.4)
    36.7 (26.7 to 46.6)
    Statistical analysis title
    Incidence of mechanical ventilation by Day 28
    Comparison groups
    Placebo Modified Intent-to-Treat (mITT) Arm v Tocilizumab (TCZ) mITT Arm
    Number of subjects included in analysis
    438
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0996
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted % difference
    Point estimate
    -6.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.8
         upper limit
    1.4
    Statistical analysis title
    Incidence of mechanical ventilation by Day 28
    Comparison groups
    TCZ - No mechanical ventilation at baseline v Placebo - No mechanical ventilation at baseline
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1355
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted % difference
    Point estimate
    -8.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -20.7
         upper limit
    3

    Secondary: Ventilator-Free Days to Day 28

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    End point title
    Ventilator-Free Days to Day 28
    End point description
    Participants who died by Day 28 were assigned 0 ventilator-free days. mITT population: Defined as all randomized participants who received any amount of study medication, with participants grouped according to the treatment assigned at randomization.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    Placebo Modified Intent-to-Treat (mITT) Arm Tocilizumab (TCZ) mITT Arm
    Number of subjects analysed
    144
    294
    Units: Days
        median (confidence interval 95%)
    16.5 (11.0 to 26.0)
    22.0 (18.0 to 28.0)
    Statistical analysis title
    Ventilator-free days to Day 28
    Comparison groups
    Placebo Modified Intent-to-Treat (mITT) Arm v Tocilizumab (TCZ) mITT Arm
    Number of subjects included in analysis
    438
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.3202
    Method
    Van Elteren test
    Parameter type
    Median difference (final values)
    Point estimate
    5.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.8
         upper limit
    13

    Secondary: Incidence of Intensive Care Unit (ICU) Stay by Day 28 (Week 4)

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    End point title
    Incidence of Intensive Care Unit (ICU) Stay by Day 28 (Week 4)
    End point description
    Participants who died by Day 28 were assumed to have required an ICU stay. mITT population: Defined as all randomized participants who received any amount of study medication, with participants grouped according to the treatment assigned at randomization.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    Placebo Modified Intent-to-Treat (mITT) Arm Tocilizumab (TCZ) mITT Arm TCZ - Not in ICU at baseline Placebo - Not in ICU at baseline
    Number of subjects analysed
    144
    294
    127
    64
    Units: Percentage of Participants
        number (confidence interval 95%)
    71.5 (64.2 to 78.9)
    66.0 (60.6 to 71.4)
    21.3 (14.1 to 28.4)
    35.9 (24.2 to 47.7)
    Statistical analysis title
    Incidence of ICU stay by Day 28
    Comparison groups
    Placebo Modified Intent-to-Treat (mITT) Arm v Tocilizumab (TCZ) mITT Arm
    Number of subjects included in analysis
    438
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1514
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted % difference
    Point estimate
    -5.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.7
         upper limit
    2.2
    Statistical analysis title
    Incidence of ICU stay by Day 28
    Comparison groups
    TCZ - Not in ICU at baseline v Placebo - Not in ICU at baseline
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.029
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted % difference
    Point estimate
    -14.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -28.6
         upper limit
    -1

    Secondary: Duration of ICU Stay to Day 28 (Week 4)

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    End point title
    Duration of ICU Stay to Day 28 (Week 4)
    End point description
    Participants who died by Day 28 were assigned a duration from the first dose of study drug to Day 28 at hour 23:59:59. mITT population: Defined as all randomized participants who received any amount of study medication, with participants grouped according to the treatment assigned at randomization.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    Placebo Modified Intent-to-Treat (mITT) Arm Tocilizumab (TCZ) mITT Arm
    Number of subjects analysed
    144
    294
    Units: Days
        median (confidence interval 95%)
    15.5 (8.7 to 25.5)
    9.8 (7.0 to 15.7)
    Statistical analysis title
    Duration of ICU stay to Day 28
    Comparison groups
    Tocilizumab (TCZ) mITT Arm v Placebo Modified Intent-to-Treat (mITT) Arm
    Number of subjects included in analysis
    438
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0454
    Method
    Van Elteren test
    Parameter type
    Median difference (final values)
    Point estimate
    -5.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15
         upper limit
    2.9

    Secondary: Clinical Status Assessed Using a 7-Category Ordinal Scale at Day 14

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    End point title
    Clinical Status Assessed Using a 7-Category Ordinal Scale at Day 14
    End point description
    Clinical status was assessed using a 7-category ordinal scale: 1 - Discharged (or "ready for discharge") 2 - Non- intensive care unit (ICU) hospital ward (or "ready for hospital ward") not requiring supplemental oxygen 3 - Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen 4 - ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen 5 - ICU, requiring intubation and mechanical ventilation 6 - ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support 7 - Death mITT population: Defined as all randomized participants who received any amount of study medication, with participants grouped according to the treatment assigned at randomization.
    End point type
    Secondary
    End point timeframe
    Day 14
    End point values
    Placebo Modified Intent-to-Treat (mITT) Arm Tocilizumab (TCZ) mITT Arm
    Number of subjects analysed
    144
    294
    Units: Percentage of Participants
    number (not applicable)
        Category 1
    29.9
    39.8
        Category 2
    4.9
    6.1
        Category 3
    11.1
    6.5
        Category 4
    7.6
    7.1
        Category 5
    16.0
    14.6
        Category 6
    17.4
    12.6
        Category 7
    13.2
    13.3
    Statistical analysis title
    Clinical status on 7-category scale at Day 14
    Comparison groups
    Placebo Modified Intent-to-Treat (mITT) Arm v Tocilizumab (TCZ) mITT Arm
    Number of subjects included in analysis
    438
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0548
    Method
    Van Elteren test
    Parameter type
    Median difference (final values)
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    0.5

    Secondary: Time to Clinical Failure to Day 28 (Week 4)

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    End point title
    Time to Clinical Failure to Day 28 (Week 4)
    End point description
    Time to clinical failure was defined as the number of days from the first dose of study drug to the first occurrence on study of death, mechanical ventilation, ICU admission, or study withdrawal prior to discharge, whichever occurs first. 9999 = Value not estimable (NE) due to an insufficient number of events. mITT population: Defined as all randomized participants who received any amount of study medication, with participants grouped according to the treatment assigned at randomization.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    Placebo Modified Intent-to-Treat (mITT) Arm Tocilizumab (TCZ) mITT Arm
    Number of subjects analysed
    144
    294
    Units: Days
        median (confidence interval 95%)
    9999 (21.0 to 9999)
    9999 (9999 to 9999)
    Statistical analysis title
    Time to clinical failure to Day 28
    Comparison groups
    Placebo Modified Intent-to-Treat (mITT) Arm v Tocilizumab (TCZ) mITT Arm
    Number of subjects included in analysis
    438
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1627
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.57
         upper limit
    1.1

    Secondary: Mortality Rate at Day 28 (week 4)

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    End point title
    Mortality Rate at Day 28 (week 4)
    End point description
    mITT population: Defined as all randomized participants who received any amount of study medication, with participants grouped according to the treatment assigned at randomization.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    Placebo Modified Intent-to-Treat (mITT) Arm Tocilizumab (TCZ) mITT Arm
    Number of subjects analysed
    144
    294
    Units: Percentage of Participants
        number (confidence interval 95%)
    19.4 (13.0 to 25.9)
    19.7 (15.2 to 24.3)
    Statistical analysis title
    Mortality rate at Day 28
    Comparison groups
    Placebo Modified Intent-to-Treat (mITT) Arm v Tocilizumab (TCZ) mITT Arm
    Number of subjects included in analysis
    438
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.941
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Weighted % difference
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.6
         upper limit
    8.2

    Secondary: Time to Recovery to Day 28 (Week 4)

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    End point title
    Time to Recovery to Day 28 (Week 4)
    End point description
    Time to recovery was defined as the number of days from the first dose of study drug to hospital discharge or "ready for discharge" (normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen) or non-ICU hospital ward or "ready for hospital ward" not requiring supplemental oxygen. Participants who died were censored at Day 28. 9999 = Value not estimable (NE) due to an insufficient number of events. mITT population: Defined as all randomized participants who received any amount of study medication, with participants grouped according to the treatment assigned at randomization.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    Placebo Modified Intent-to-Treat (mITT) Arm Tocilizumab (TCZ) mITT Arm
    Number of subjects analysed
    144
    294
    Units: Days
        median (confidence interval 95%)
    24.0 (18.0 to 9999)
    16.0 (12.0 to 21.0)
    Statistical analysis title
    Time to recovery to Day 28
    Comparison groups
    Placebo Modified Intent-to-Treat (mITT) Arm v Tocilizumab (TCZ) mITT Arm
    Number of subjects included in analysis
    438
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0528
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.307
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1
         upper limit
    1.72

    Secondary: Duration of Supplemental Oxygen to Day 28 (Week 4)

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    End point title
    Duration of Supplemental Oxygen to Day 28 (Week 4)
    End point description
    Participants who died by Day 28 were assigned a duration of 28 days of supplemental oxygen. mITT population: Defined as all randomized participants who received any amount of study medication, with participants grouped according to the treatment assigned at randomization.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    Placebo Modified Intent-to-Treat (mITT) Arm Tocilizumab (TCZ) mITT Arm
    Number of subjects analysed
    144
    294
    Units: Days
        median (confidence interval 95%)
    28.0 (26.0 to 28.0)
    26.5 (19.0 to 28.0)
    Statistical analysis title
    Duration of supplemental oxygen to Day 28
    Comparison groups
    Placebo Modified Intent-to-Treat (mITT) Arm v Tocilizumab (TCZ) mITT Arm
    Number of subjects included in analysis
    438
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0477
    Method
    Van Elteren test
    Parameter type
    Median difference (final values)
    Point estimate
    -1.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9
         upper limit
    0.5

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    60 days
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Placebo Arm (Safety-Evaluable Population)
    Reporting group description
    All participants who received any amount of study medication. Participants are grouped according to the treatment first received rather than the treatment assigned at randomization.

    Reporting group title
    Tocilizumab (TCZ) Arm (Safety-Evaluable Population)
    Reporting group description
    All participants who received any amount of study medication. Participants are grouped according to the treatment first received rather than the treatment assigned at randomization.

    Serious adverse events
    Placebo Arm (Safety-Evaluable Population) Tocilizumab (TCZ) Arm (Safety-Evaluable Population)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    64 / 143 (44.76%)
    116 / 295 (39.32%)
         number of deaths (all causes)
    36
    72
         number of deaths resulting from adverse events
    Vascular disorders
    Arterial haemorrhage
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypertension
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 143 (0.70%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral embolism
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 143 (0.70%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 143 (0.70%)
    5 / 295 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    1 / 5
    Pyrexia
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 143 (1.40%)
    4 / 295 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Acute respiratory failure
         subjects affected / exposed
    2 / 143 (1.40%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Aspiration
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    3 / 143 (2.10%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung consolidation
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal haemorrhage
         subjects affected / exposed
    2 / 143 (1.40%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    3 / 143 (2.10%)
    4 / 295 (1.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         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
    2 / 143 (1.40%)
    5 / 295 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Respiratory disorder
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    6 / 143 (4.20%)
    5 / 295 (1.69%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 143 (0.70%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Citrobacter test positive
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcus test positive
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transfusion-related acute lung injury
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 143 (0.70%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 143 (0.00%)
    3 / 295 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bundle branch block right
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    5 / 143 (3.50%)
    4 / 295 (1.36%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Cardiac ventricular thrombosis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 143 (0.00%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulseless electrical activity
         subjects affected / exposed
    2 / 143 (1.40%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic transformation stroke
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Seizure
         subjects affected / exposed
    1 / 143 (0.70%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Coagulopathy
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Eosinophilia
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 143 (0.00%)
    4 / 295 (1.36%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 143 (0.70%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia perforation
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 143 (0.70%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    0 / 143 (0.00%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Small intestinal obstruction
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic hepatitis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 143 (2.80%)
    10 / 295 (3.39%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal failure
         subjects affected / exposed
    2 / 143 (1.40%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Compartment syndrome
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    3 / 143 (2.10%)
    3 / 295 (1.02%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 143 (0.00%)
    3 / 295 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    2 / 143 (1.40%)
    14 / 295 (4.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 14
         deaths causally related to treatment / all
    0 / 2
    0 / 13
    COVID-19 pneumonia
         subjects affected / exposed
    20 / 143 (13.99%)
    36 / 295 (12.20%)
         occurrences causally related to treatment / all
    0 / 20
    0 / 36
         deaths causally related to treatment / all
    0 / 20
    0 / 36
    Candida infection
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus hepatitis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter pneumonia
         subjects affected / exposed
    1 / 143 (0.70%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 143 (2.80%)
    7 / 295 (2.37%)
         occurrences causally related to treatment / all
    3 / 5
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    2 / 143 (1.40%)
    6 / 295 (2.03%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia escherichia
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 143 (0.70%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 143 (2.80%)
    3 / 295 (1.02%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    7 / 143 (4.90%)
    7 / 295 (2.37%)
         occurrences causally related to treatment / all
    3 / 8
    3 / 7
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    Staphylococcal infection
         subjects affected / exposed
    1 / 143 (0.70%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stenotrophomonas infection
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis bacterial
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 143 (0.00%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 143 (0.70%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Arm (Safety-Evaluable Population) Tocilizumab (TCZ) Arm (Safety-Evaluable Population)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 143 (20.28%)
    83 / 295 (28.14%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 143 (2.10%)
    20 / 295 (6.78%)
         occurrences all number
    4
    24
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 143 (6.99%)
    17 / 295 (5.76%)
         occurrences all number
    10
    17
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    8 / 143 (5.59%)
    18 / 295 (6.10%)
         occurrences all number
    8
    18
    Diarrhoea
         subjects affected / exposed
    3 / 143 (2.10%)
    18 / 295 (6.10%)
         occurrences all number
    3
    18
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    8 / 143 (5.59%)
    10 / 295 (3.39%)
         occurrences all number
    12
    10
    Urinary tract infection
         subjects affected / exposed
    5 / 143 (3.50%)
    22 / 295 (7.46%)
         occurrences all number
    6
    22

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Apr 2020
    Removed secondary efficacy objective; updated eligibility criteria; updated text for time to clinical failure outcome measure; clarification text for ordinal scale interpretation.
    11 Jun 2020
    Added secondary efficacy endpoint; defined key secondary 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
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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