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    Clinical Trial Results:
    A phase III, randomized, double-blind, multicenter study to evaluate the efficacy and safety of remdesivir plus tocilizumab compared with remdesivir plus placebo in hospitalized patients with severe COVID-19 pneumonia

    Summary
    EudraCT number
    		 2020-002275-34
    Trial protocol
    		 ES  
    Global end of trial date
    08 Mar 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Mar 2022
    First version publication date
    16 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    WA42511
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04409262
    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, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +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
    23 Apr 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was a Phase III, randomized, double-blind, multicenter study to assess the efficacy and safety of tocilizumab plus remdesivir (TCZ+RDV) compared with placebo plus remdesivir (PBO+RDV) in hospitalized patients with severe COVID-19 pneumonia.
    Protection of trial subjects
    All subjects were required to sign an Informed Consent Form (ICF).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Jun 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 154
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    Russian Federation: 49
    Country: Number of subjects enrolled
    United States: 432
    Worldwide total number of subjects
    649
    EEA total number of subjects
    14
    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)
    400
    From 65 to 84 years
    238
    85 years and over
    11

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants with severe COVID-19 pneumonia

    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
    		 Remdesivir + Tocilizumab (RDV+TCZ)
    Arm description
    		 Participants were to receive a 200 mg intravenous (IV) loading dose of RDV, followed by one infusion of TCZ on Day 1. Participants were then to be given a 100 mg once daily IV maintenance dose of RDV from Days 2-10, with discontinuation at discharge whether or not 10 days of RDV dosing were completed. One additional infusion of TCZ was allowed 8-24 hours after the first for participants with sustained fever or clinically significant worsening of signs or symptoms.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remdesivir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg IV loading dose, followed by a 100 mg once-daily IV maintenance dose from Days 2-10.

    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
    One IV TCZ infusion at a dose of 8 mg/kg to a maximum of 800 mg per dose. One additional infusion of TCZ was allowed 8-24 hours after the first for participants with sustained fever or clinically significant worsening of signs or symptoms.

    Arm title
    		 Remdesivir + Placebo (RDV+Placebo)
    Arm description
    		 Participants were to receive a 200 mg intravenous (IV) loading dose of RDV, followed by one infusion of PBO on Day 1. Participants were then to be given a 100 mg once daily IV maintenance dose of RDV from Days 2-10, with discontinuation at discharge whether or not 10 days of RDV dosing were completed. One additional infusion of PBO was allowed 8-24 hours after the first for participants with sustained fever or clinically significant worsening of signs or symptoms.
    Arm type
    		 Placebo

    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
    One IV infusion of placebo. One additional infusion of IV placebo was allowed 8-24 hours after the first for participants with sustained fever or clinically significant worsening of signs or symptoms.

    Investigational medicinal product name
    Remdesivir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg IV loading dose, followed by a 100 mg once-daily IV maintenance dose from Days 2-10

    Number of subjects in period 1
    		Remdesivir + Tocilizumab (RDV+TCZ) Remdesivir + Placebo (RDV+Placebo)
    Started
    434
    215
    Completed
    300
    140
    Not completed
    134
    75
         Consent withdrawn by subject
    10
    5
         Adverse Event
    2
    -
         Death
    97
    55
         Lost to follow-up
    23
    12
         Lack of Staff
    1
    -
         Protocol deviation
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Remdesivir + Tocilizumab (RDV+TCZ)
    Reporting group description
    		 Participants were to receive a 200 mg intravenous (IV) loading dose of RDV, followed by one infusion of TCZ on Day 1. Participants were then to be given a 100 mg once daily IV maintenance dose of RDV from Days 2-10, with discontinuation at discharge whether or not 10 days of RDV dosing were completed. One additional infusion of TCZ was allowed 8-24 hours after the first for participants with sustained fever or clinically significant worsening of signs or symptoms.

    Reporting group title
    Remdesivir + Placebo (RDV+Placebo)
    Reporting group description
    		 Participants were to receive a 200 mg intravenous (IV) loading dose of RDV, followed by one infusion of PBO on Day 1. Participants were then to be given a 100 mg once daily IV maintenance dose of RDV from Days 2-10, with discontinuation at discharge whether or not 10 days of RDV dosing were completed. One additional infusion of PBO was allowed 8-24 hours after the first for participants with sustained fever or clinically significant worsening of signs or symptoms.

    Reporting group values
    		 Remdesivir + Tocilizumab (RDV+TCZ) Remdesivir + Placebo (RDV+Placebo) Total
    Number of subjects
    		 434 215 649
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 259 141 400
        From 65-84 years
    		 167 71 238
        85 years and over
    		 8 3 11
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.1 ± 13.3 58.2 ± 13.6 -
    Gender categorical
    Units: Subjects
        Female
    		 167 73 240
        Male
    		 267 142 409
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 4 4 8
        Asian
    		 17 5 22
        Native Hawaiian or Other Pacific Islander
    		 7 3 10
        Black or African American
    		 52 20 72
        White
    		 282 154 436
        More than one race
    		 9 2 11
        Unknown or Not Reported
    		 63 27 90
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 209 125 334
        Not Hispanic or Latino
    		 208 88 296
        Unknown or Not Reported
    		 17 2 19

    End points

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    End points reporting groups
    Reporting group title
    Remdesivir + Tocilizumab (RDV+TCZ)
    Reporting group description
    		 Participants were to receive a 200 mg intravenous (IV) loading dose of RDV, followed by one infusion of TCZ on Day 1. Participants were then to be given a 100 mg once daily IV maintenance dose of RDV from Days 2-10, with discontinuation at discharge whether or not 10 days of RDV dosing were completed. One additional infusion of TCZ was allowed 8-24 hours after the first for participants with sustained fever or clinically significant worsening of signs or symptoms.

    Reporting group title
    Remdesivir + Placebo (RDV+Placebo)
    Reporting group description
    		 Participants were to receive a 200 mg intravenous (IV) loading dose of RDV, followed by one infusion of PBO on Day 1. Participants were then to be given a 100 mg once daily IV maintenance dose of RDV from Days 2-10, with discontinuation at discharge whether or not 10 days of RDV dosing were completed. One additional infusion of PBO was allowed 8-24 hours after the first for participants with sustained fever or clinically significant worsening of signs or symptoms.

    Subject analysis set title
    Remdesivir + Placebo (RDV+Placebo) - mITT population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The mITT population included all randomized participants who received any amount of TCZ or placebo (PBO), with participants grouped according to treatment assigned at randomization.

    Subject analysis set title
    Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The mITT population included all randomized participants who received any amount of TCZ or placebo (PBO), with participants grouped according to treatment assigned at randomization.

    Subject analysis set title
    Remdesivir + Placebo (RDV+Placebo) - safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis population consisted of all participants who received any amount of study medication (RDV and/or TCZ/PBO). Participants were grouped according to the treatment received rather than by the treatment assigned at randomization. Participants that only received RDV and did not receive TCZ/PBO were included in the RDV+PBO arm of the safety population.

    Subject analysis set title
    Remdesivir + Tocilizumab (RDV+TCZ) - safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis population consisted of all participants who received any amount of study medication (RDV and/or TCZ/PBO). Participants were grouped according to the treatment received rather than by the treatment assigned at randomization. Participants that only received RDV and did not receive TCZ/PBO were included in the RDV+PBO arm of the safety population.

    Primary: Time to hospital discharge or "ready for discharge" up to Day 28

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    End point title
    		 Time to hospital discharge or "ready for discharge" up to Day 28
    End point description
    Defined as days from randomization to hospital discharge or “Ready for Discharge” not followed by ordinal scale category >1, hospital readmission or death. Hospital discharge or "Ready for Discharge" is defined as an ordinal score of 1 on the 7-point ordinal scale. Participants who die are censored at Day 28. 1. Discharged (or "ready for discharge" as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen) 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 (e.g., vasopressors, renal replacement therapy) 7. Death
    End point type
    Primary
    End point timeframe
    Up to Day 28
    End point values
    		 Remdesivir + Placebo (RDV+Placebo) - mITT population Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects analysed
    210
    430
    Units: days
        median (confidence interval 95%)
    14.0 (11.0 to 16.0)
    14.0 (12.0 to 15.0)
    Statistical analysis title
    		 Analysis
    Comparison groups
    Remdesivir + Placebo (RDV+Placebo) - mITT population v Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7414
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.965
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.19

    Secondary: Time to mechanical ventilation or death up to Day 28

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    End point title
    		 Time to mechanical ventilation or death up to Day 28
    End point description
    Time to Mechanical Ventilation or Death defined as the time from randomization to the first occurrence of death or mechanical ventilation. For participants already on mechanical ventilation at baseline, only death is counted as an event.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    		 Remdesivir + Placebo (RDV+Placebo) - mITT population Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects analysed
    210 [1]
    430 [2]
    Units: days
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [1] - 9999 = endpoint not estimable due to insufficient number of events
    [2] - 9999 = endpoint not estimable due to insufficient number of events
    Statistical analysis title
    		 Analysis
    Comparison groups
    Remdesivir + Placebo (RDV+Placebo) - mITT population v Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8993
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.34

    Secondary: Clinical status as assessed by the investigator using a 7-category ordinal scale of clinical status on Day 14

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    End point title
    		 Clinical status as assessed by the investigator using a 7-category ordinal scale of clinical status on Day 14
    End point description
    Clinical status was assessed by the investigator according to the following ordinal scale categories: 1. Discharged (or "ready for discharge" as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen) 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 (e.g., vasopressors, renal replacement therapy) 7. Death
    End point type
    Secondary
    End point timeframe
    Day 14
    End point values
    		 Remdesivir + Placebo (RDV+Placebo) - mITT population Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects analysed
    210
    428 [3]
    Units: Percentage of participants
    number (not applicable)
        Category 1
    52.4
    54.0
        Category 2
    1.9
    2.6
        Category 3
    11.4
    8.9
        Category 4
    6.7
    9.6
        Category 5
    6.7
    4.9
        Category 6
    11.4
    10.0
        Category 7
    9.5
    10.0
    Notes
    [3] - Two participants had no post-baseline clinical status data to Day 14 and were excluded from analysis
    Statistical analysis title
    		 Analysis
    Comparison groups
    Remdesivir + Placebo (RDV+Placebo) - mITT population v Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7648
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.44

    Secondary: Time to death up to Day 28

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    End point title
    		 Time to death up to Day 28
    End point description
    Time to death is defined as the time from randomization to death.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    		 Remdesivir + Placebo (RDV+Placebo) - mITT population Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects analysed
    210 [4]
    430 [5]
    Units: Days
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [4] - 9999 = endpoint not estimable due to insufficient number of events
    [5] - 9999 = endpoint not estimable due to insufficient number of events
    Statistical analysis title
    		 Analysis
    Comparison groups
    Remdesivir + Placebo (RDV+Placebo) - mITT population v Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7867
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.948
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.39

    Secondary: Time to death up to Day 60

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    End point title
    		 Time to death up to Day 60
    End point description
    Time to death is defined as the time from randomization to death.
    End point type
    Secondary
    End point timeframe
    Up to Day 60
    End point values
    		 Remdesivir + Placebo (RDV+Placebo) - mITT population Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects analysed
    210 [6]
    430 [7]
    Units: Days
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [6] - 9999 = endpoint not estimable due to insufficient number of events
    [7] - 9999 = endpoint not estimable due to insufficient number of events
    Statistical analysis title
    		 Analysis
    Comparison groups
    Remdesivir + Placebo (RDV+Placebo) - mITT population v Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4602
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.882
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 1.23

    Secondary: Time to improvement of at least 2 categories relative to baseline on a 7-category ordinal scale of clinical status up to Day 28

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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 up to Day 28
    End point description
    Defined as time from randomization to the time when at least a 2-category improvement in the 7-category ordinal scale is observed. Patients who die are censored at day 28. Clinical status was assessed by the investigator according to the following ordinal scale categories: 1. Discharged (or "ready for discharge" as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen) 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 (e.g., vasopressors, renal replacement therapy) 7. Death
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    		 Remdesivir + Placebo (RDV+Placebo) - mITT population Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects analysed
    210
    430
    Units: Days
        median (confidence interval 95%)
    11.0 (10.0 to 13.0)
    12.0 (11.0 to 13.0)
    Statistical analysis title
    		 Analysis
    Comparison groups
    Remdesivir + Placebo (RDV+Placebo) - mITT population v Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8664
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.982
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.21

    Secondary: Clinical status as assessed by the investigator using a 7-category ordinal scale of clinical status on Day 7

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    End point title
    		 Clinical status as assessed by the investigator using a 7-category ordinal scale of clinical status on Day 7
    End point description
    Clinical status was assessed by the investigator according to the following ordinal scale categories: 1. Discharged (or "ready for discharge" as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen) 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 (e.g., vasopressors, renal replacement therapy) 7. Death
    End point type
    Secondary
    End point timeframe
    Day 7
    End point values
    		 Remdesivir + Placebo (RDV+Placebo) - mITT population Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects analysed
    210
    428 [8]
    Units: Percentage of participants
    number (not applicable)
        Category 1
    21.9
    19.4
        Category 2
    4.3
    5.6
        Category 3
    17.6
    20.1
        Category 4
    30.0
    29.4
        Category 5
    9.5
    10.0
        Category 6
    12.9
    12.1
        Category 7
    3.8
    3.3
    Notes
    [8] - Two participants had no post-baseline clinical status data to Day 7 and were excluded from analysis.
    Statistical analysis title
    		 Analysis
    Comparison groups
    Remdesivir + Placebo (RDV+Placebo) - mITT population v Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9569
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.35

    Secondary: Clinical status as assessed by the investigator using a 7-category ordinal scale of clinical status on Day 21

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    End point title
    		 Clinical status as assessed by the investigator using a 7-category ordinal scale of clinical status on Day 21
    End point description
    Clinical status was assessed by the investigator according to the following ordinal scale categories: 1. Discharged (or "ready for discharge" as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen) 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 (e.g., vasopressors, renal replacement therapy) 7. Death
    End point type
    Secondary
    End point timeframe
    Day 21
    End point values
    		 Remdesivir + Placebo (RDV+Placebo) - mITT population Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects analysed
    210
    428 [9]
    Units: Percentage of participants
    number (not applicable)
        Category 1
    62.4
    64.3
        Category 2
    1.4
    1.2
        Category 3
    4.8
    4.7
        Category 4
    2.9
    4.4
        Category 5
    6.7
    5.6
        Category 6
    7.1
    5.8
        Category 7
    14.8
    14.0
    Notes
    [9] - Two participants had no post-baseline clinical status data to Day 21 and were excluded from analysis
    Statistical analysis title
    		 Analysis
    Comparison groups
    Remdesivir + Placebo (RDV+Placebo) - mITT population v Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6331
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.52

    Secondary: Clinical status as assessed by the investigator using a 7-category ordinal scale of clinical status on Day 28

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    End point title
    		 Clinical status as assessed by the investigator using a 7-category ordinal scale of clinical status on Day 28
    End point description
    Clinical status was assessed by the investigator according to the following ordinal scale categories: 1. Discharged (or "ready for discharge" as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen) 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 (e.g., vasopressors, renal replacement therapy) 7. Death
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Remdesivir + Placebo (RDV+Placebo) - mITT population Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects analysed
    210
    428 [10]
    Units: Percentage of participants
    number (not applicable)
        Category 1
    67.1
    66.4
        Category 2
    1.4
    1.4
        Category 3
    1.0
    3.5
        Category 4
    2.9
    3.0
        Category 5
    4.3
    3.7
        Category 6
    3.8
    3.7
        Category 7
    19.5
    18.2
    Notes
    [10] - Two participants had no post-baseline clinical status data to Day 28 and were excluded from analysis
    Statistical analysis title
    		 Analysis
    Comparison groups
    Remdesivir + Placebo (RDV+Placebo) - mITT population v Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9622
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.4

    Secondary: Clinical status as assessed by the investigator using a 7-category ordinal scale of clinical status on Day 60

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    End point title
    		 Clinical status as assessed by the investigator using a 7-category ordinal scale of clinical status on Day 60
    End point description
    Clinical status was assessed by the investigator according to the following ordinal scale categories: 1. Discharged (or "ready for discharge" as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen) 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 (e.g., vasopressors, renal replacement therapy) 7. Death
    End point type
    Secondary
    End point timeframe
    Day 60
    End point values
    		 Remdesivir + Placebo (RDV+Placebo) - mITT population Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects analysed
    210
    428 [11]
    Units: Percentage of participants
    number (not applicable)
        Category 1
    70.0
    72.2
        Category 2
    1.4
    0.7
        Category 3
    1.0
    1.4
        Category 4
    1.4
    1.6
        Category 5
    0.5
    0.7
        Category 6
    0
    0.7
        Category 7
    25.7
    22.7
    Notes
    [11] - Two participants had no post-baseline clinical status data to Day 60 and were excluded from analysis
    Statistical analysis title
    		 Analysis
    Comparison groups
    Remdesivir + Placebo (RDV+Placebo) - mITT population v Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.485
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.64

    Secondary: Proportion of participants requiring initiation of mechanical ventilation post-baseline at Day 28 and Day 60 (participants who did not require mechanical ventilation at baseline)

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    End point title
    		 Proportion of participants requiring initiation of mechanical ventilation post-baseline at Day 28 and Day 60 (participants who did not require mechanical ventilation at baseline)
    End point description
    Day 28: Participants who withdraw or die prior to Day 28 are assumed to have required mechanical ventilation. Participants without mechanical ventilation prior to discharge are assumed not to have required mechanical ventilation unless they die by Day 28, which are counted as an event. Day 60: Participants who withdraw or die prior to Day 60 are assumed to have required mechanical ventilation. Participants without mechanical ventilation prior to discharge are assumed not to have required mechanical ventilation unless they die by Day 60, which are counted as an event.
    End point type
    Secondary
    End point timeframe
    Day 28 and Day 60
    End point values
    		 Remdesivir + Placebo (RDV+Placebo) - mITT population Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects analysed
    188 [12]
    371 [13]
    Units: Percentage of participants
    number (confidence interval 95%)
        Day 28
    29.8 (23.3 to 36.3)
    27.5 (23.0 to 32.0)
        Day 60
    31.4 (24.7 to 38.0)
    28.8 (24.2 to 33.5)
    Notes
    [12] - Analysis population included only participants not on mechanical ventilation at baseline
    [13] - Analysis population included only participants not on mechanical ventilation at baseline
    Statistical analysis title
    		 Day 60
    Comparison groups
    Remdesivir + Placebo (RDV+Placebo) - mITT population v Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5494
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Weighted % difference
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.5
         upper limit
    		 5.6
    Statistical analysis title
    		 Day 28
    Comparison groups
    Remdesivir + Placebo (RDV+Placebo) - mITT population v Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5915
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Weighted % difference
    Point estimate
    -2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.2
         upper limit
    		 5.9

    Secondary: Proportion of participants who are alive and free of respiratory failure at Day 28 and Day 60 (participants requiring mechanical ventilation at baseline)

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    End point title
    		 Proportion of participants who are alive and free of respiratory failure at Day 28 and Day 60 (participants requiring mechanical ventilation at baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28 and Day 60
    End point values
    		 Remdesivir + Placebo (RDV+Placebo) - mITT population Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects analysed
    22 [14]
    59 [15]
    Units: Percentage of participants
    number (confidence interval 95%)
        Day 28
    54.5 (33.7 to 75.4)
    40.7 (28.1 to 53.2)
        Day 60
    63.6 (43.5 to 83.7)
    47.5 (34.7 to 60.2)
    Notes
    [14] - Analysis population included only participants on mechanical ventilation at baseline
    [15] - Analysis population included only participants on mechanical ventilation at baseline
    Statistical analysis title
    		 Day 60
    Comparison groups
    Remdesivir + Placebo (RDV+Placebo) - mITT population v Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.229
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Weighted % difference
    Point estimate
    -14.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37
         upper limit
    		 7.8
    Statistical analysis title
    		 Day 28
    Comparison groups
    Remdesivir + Placebo (RDV+Placebo) - mITT population v Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.259
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Weighted % difference
    Point estimate
    -14.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37.4
         upper limit
    		 9.2

    Secondary: Duration of mechanical ventilation (participants requiring mechanical ventilation at baseline) up to Day 28

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    End point title
    		 Duration of mechanical ventilation (participants requiring mechanical ventilation at baseline) up to Day 28
    End point description
    Participants who die by Day 28 are assigned a duration of 28 days.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    		 Remdesivir + Placebo (RDV+Placebo) - mITT population Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects analysed
    22 [16]
    59 [17]
    Units: Days
        arithmetic mean (confidence interval 95%)
    16.7 (11.9 to 21.5)
    19.6 (16.8 to 22.4)
    Notes
    [16] - Analysis population included only participants on mechanical ventilation at baseline
    [17] - Analysis population included only participants on mechanical ventilation at baseline
    Statistical analysis title
    		 Analysis
    Comparison groups
    Remdesivir + Placebo (RDV+Placebo) - mITT population v Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2434
    Method
    		 Regression, Linear
    Parameter type
    		 Difference in means
    Point estimate
    3.1125
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.16
         upper limit
    		 8.38

    Secondary: Difference in Mortality at Days 14, 28, and 60

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    End point title
    		 Difference in Mortality at Days 14, 28, and 60
    End point description
    End point type
    Secondary
    End point timeframe
    Days 14, 28, and 60
    End point values
    		 Remdesivir + Placebo (RDV+Placebo) - mITT population Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects analysed
    210
    430
    Units: Percentage of participants
    number (confidence interval 95%)
        Day 14
    9.5 (5.6 to 13.5)
    10.0 (7.2 to 12.8)
        Day 28
    19.5 (14.2 to 24.9)
    18.1 (14.5 to 21.8)
        Day 60
    25.7 (19.8 to 31.6)
    22.6 (18.6 to 26.5)
    Statistical analysis title
    		 Day 14
    Comparison groups
    Remdesivir + Placebo (RDV+Placebo) - mITT population v Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8222
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Weighted % difference
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.4
         upper limit
    		 5.6
    Statistical analysis title
    		 Day 28
    Comparison groups
    Remdesivir + Placebo (RDV+Placebo) - mITT population v Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6944
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Weighted % difference
    Point estimate
    -1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.8
         upper limit
    		 5.2
    Statistical analysis title
    		 Day 60
    Comparison groups
    Remdesivir + Placebo (RDV+Placebo) - mITT population v Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3919
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Weighted % difference
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.1
         upper limit
    		 4

    Secondary: Time to recovery up to Day 28

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    End point title
    		 Time to recovery up to Day 28
    End point description
    Defined as the time from randomization to the time when an ordinal scale category of 2 (non-ICU hospital ward or “ready for hospital ward” not requiring supplemental oxygen) or better is observed, not followed by ordinal scale category >2 or death. Participants who die are censored at day 28. 1. Discharged (or "ready for discharge" as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen) 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 (e.g., vasopressors, renal replacement therapy) 7. Death
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    		 Remdesivir + Placebo (RDV+Placebo) - mITT population Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects analysed
    210
    430
    Units: Days
        median (confidence interval 95%)
    13.0 (10.0 to 15.0)
    13.0 (11.0 to 14.0)
    Statistical analysis title
    		 Analysis
    Comparison groups
    Remdesivir + Placebo (RDV+Placebo) - mITT population v Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6778
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.957
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.18

    Secondary: Proportion of participants who are discharged or "ready for discharge" up to Day 28

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    End point title
    		 Proportion of participants who are discharged or "ready for discharge" up to Day 28
    End point description
    Defined as hospital discharge or "Ready for Discharge" not followed by ordinal scale category >1, hospital readmission or death. 1. Discharged (or "ready for discharge" as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen) 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 machanical ventilation and additional organ support (e.g., vasopressors, renal replacement therapy) 7. Death
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    		 Remdesivir + Placebo (RDV+Placebo) - mITT population Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects analysed
    210
    430
    Units: Percentage of participants
        number (confidence interval 95%)
    67.1 (60.8 to 73.5)
    66.0 (61.6 to 70.5)
    Statistical analysis title
    		 Analysis
    Comparison groups
    Remdesivir + Placebo (RDV+Placebo) - mITT population v Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7692
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Weighted % difference
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.7
         upper limit
    		 6.8

    Secondary: Proportion of participants who require initiation of mechanical ventilation post-baseline or die up to Day 28

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    End point title
    		 Proportion of participants who require initiation of mechanical ventilation post-baseline or die up to Day 28
    End point description
    Participants already on mechanical ventilation at baseline are only counted as an event if death occurs.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    		 Remdesivir + Placebo (RDV+Placebo) - mITT population Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects analysed
    210
    430
    Units: Percentage of participants
        number (confidence interval 95%)
    29.0 (22.9 to 35.2)
    28.6 (24.3 to 32.9)
    Statistical analysis title
    		 Analysis
    Comparison groups
    Remdesivir + Placebo (RDV+Placebo) - mITT population v Remdesivir + Tocilizumab (RDV+TCZ) - mITT population
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9334
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Weighted % difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.8
         upper limit
    		 7.2

    Other pre-specified: Percentage of Participants with Adverse Events (AEs) Tabulated by Severity

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    End point title
    		 Percentage of Participants with Adverse Events (AEs) Tabulated by Severity
    End point description
    AEs were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL) Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL Grade 4: Life-threatening consequences; urgent intervention indicated Grade 5: Death related to AE Participants are counted at the highest AE grade experienced. Participants that only received RDV and did not receive TCZ/PBO were included in the RDV+PBO arm of the safety population.
    End point type
    Other pre-specified
    End point timeframe
    Up to Day 60
    End point values
    		 Remdesivir + Placebo (RDV+Placebo) - safety population Remdesivir + Tocilizumab (RDV+TCZ) - safety population
    Number of subjects analysed
    213
    429
    Units: Percentage of participants
    number (not applicable)
        Grade 1
    9.9
    10.5
        Grade 2
    21.1
    28.2
        Grade 3
    10.3
    11.2
        Grade 4
    4.2
    4.9
        Grade 5
    25.8
    22.6
    No statistical analyses for this end point

    Other pre-specified: Proportion of Participants with any Post-Treatment Infection

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    End point title
    		 Proportion of Participants with any Post-Treatment Infection
    End point description
    Participants that only received RDV and did not receive TCZ/PBO were included in the RDV+PBO arm of the safety population.
    End point type
    Other pre-specified
    End point timeframe
    Up to Day 60
    End point values
    		 Remdesivir + Placebo (RDV+Placebo) - safety population Remdesivir + Tocilizumab (RDV+TCZ) - safety population
    Number of subjects analysed
    213
    429
    Units: Percentage of Participants
    number (not applicable)
        Serious infections
    27.7
    22.6
        Infections
    35.7
    33.3
        Opportunistic infections
    2.3
    1.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 60 days
    Adverse event reporting additional description
    The safety analysis population consisted of all participants who received any amount of study medication (RDV and/or TCZ/PBO). Participants were grouped according to treatment received rather than treatment assigned at randomization. Participants that only received RDV and not TCZ/PBO were included in the RDV+PBO arm of the safety population.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    REMDESIVIR + TOCILIZUMAB
    Reporting group description
    		 The safety analysis population consisted of all participants who received any amount of study medication (RDV and/or TCZ/PBO). Participants were grouped according to the treatment received rather than by the treatment assigned at randomization. Participants that only received RDV and did not receive TCZ/PBO were included in the RDV+PBO arm of the safety population.

    Reporting group title
    REMDESIVIR + PLACEBO
    Reporting group description
    		 The safety analysis population consisted of all participants who received any amount of study medication (RDV and/or TCZ/PBO). Participants were grouped according to the treatment received rather than by the treatment assigned at randomization. Participants that only received RDV and did not receive TCZ/PBO were included in the RDV+PBO arm of the safety population.

    Serious adverse events
    		 REMDESIVIR + TOCILIZUMAB REMDESIVIR + PLACEBO
    Total subjects affected by serious adverse events
         subjects affected / exposed
    141 / 429 (32.87%)
    76 / 213 (35.68%)
         number of deaths (all causes)
    97
    55
         number of deaths resulting from adverse events
    11
    2
    Vascular disorders
    Aortic thrombosis
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         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
    1 / 429 (0.23%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 429 (0.23%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemodynamic instability
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypovolaemic shock
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    4 / 429 (0.93%)
    4 / 213 (1.88%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    4 / 429 (0.93%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    2 / 429 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    General disorders and administration site conditions
    Brain death
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Catheter site haemorrhage
         subjects affected / exposed
    2 / 429 (0.47%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 429 (0.47%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Hypothermia
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 429 (0.47%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 2
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    3 / 429 (0.70%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    5 / 429 (1.17%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    3 / 429 (0.70%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumothorax
         subjects affected / exposed
    7 / 429 (1.63%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    2 / 429 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    5 / 429 (1.17%)
    3 / 213 (1.41%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 429 (0.23%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood culture positive
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 429 (0.23%)
    3 / 213 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Brain herniation
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    Atrioventricular block complete
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         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
    2 / 429 (0.47%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 429 (0.23%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 429 (0.47%)
    3 / 213 (1.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    3 / 429 (0.70%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 429 (0.23%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic left ventricular failure
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         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
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular dysfunction
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    2 / 429 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Brain compression
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    5 / 429 (1.17%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Encephalopathy
         subjects affected / exposed
    5 / 429 (1.17%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 429 (0.00%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemorrhagic transformation stroke
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 429 (0.23%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    1 / 429 (0.23%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neurotoxicity
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (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
    Blood loss anaemia
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 429 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bicytopenia
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heparin-induced thrombocytopenia
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Normocytic anaemia
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 429 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal wall haematoma
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diverticular perforation
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    2 / 429 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 429 (0.23%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Pneumoperitoneum
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    3 / 429 (0.70%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    2 / 429 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 429 (0.23%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous emphysema
         subjects affected / exposed
    2 / 429 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    21 / 429 (4.90%)
    14 / 213 (6.57%)
         occurrences causally related to treatment / all
    5 / 21
    1 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal failure
         subjects affected / exposed
    5 / 429 (1.17%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 429 (0.23%)
    5 / 213 (2.35%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 429 (0.00%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    2 / 429 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    14 / 429 (3.26%)
    8 / 213 (3.76%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 8
         deaths causally related to treatment / all
    0 / 14
    0 / 8
    COVID-19 pneumonia
         subjects affected / exposed
    36 / 429 (8.39%)
    27 / 213 (12.68%)
         occurrences causally related to treatment / all
    0 / 36
    0 / 27
         deaths causally related to treatment / all
    0 / 35
    0 / 26
    Enterobacter infection
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter bacteraemia
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungaemia
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (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
    21 / 429 (4.90%)
    6 / 213 (2.82%)
         occurrences causally related to treatment / all
    13 / 22
    4 / 6
         deaths causally related to treatment / all
    1 / 6
    0 / 1
    Pneumonia acinetobacter
         subjects affected / exposed
    2 / 429 (0.47%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    5 / 429 (1.17%)
    4 / 213 (1.88%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia klebsiella
         subjects affected / exposed
    1 / 429 (0.23%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    11 / 429 (2.56%)
    6 / 213 (2.82%)
         occurrences causally related to treatment / all
    6 / 13
    2 / 7
         deaths causally related to treatment / all
    2 / 5
    0 / 2
    Septic shock
         subjects affected / exposed
    23 / 429 (5.36%)
    10 / 213 (4.69%)
         occurrences causally related to treatment / all
    9 / 23
    4 / 10
         deaths causally related to treatment / all
    4 / 13
    1 / 3
    Pulmonary sepsis
         subjects affected / exposed
    1 / 429 (0.23%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    1 / 429 (0.23%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    0 / 429 (0.00%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 429 (0.23%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 429 (0.93%)
    3 / 213 (1.41%)
         occurrences causally related to treatment / all
    4 / 4
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 429 (0.00%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Vascular device infection
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 213 (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
    		 REMDESIVIR + TOCILIZUMAB REMDESIVIR + PLACEBO
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    144 / 429 (33.57%)
    70 / 213 (32.86%)
    Investigations
    Transaminases increased
         subjects affected / exposed
    25 / 429 (5.83%)
    10 / 213 (4.69%)
         occurrences all number
    25
    10
    Vascular disorders
    Hypotension
         subjects affected / exposed
    19 / 429 (4.43%)
    12 / 213 (5.63%)
         occurrences all number
    19
    12
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    13 / 429 (3.03%)
    14 / 213 (6.57%)
         occurrences all number
    13
    15
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    54 / 429 (12.59%)
    25 / 213 (11.74%)
         occurrences all number
    54
    25
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    24 / 429 (5.59%)
    11 / 213 (5.16%)
         occurrences all number
    25
    11
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    20 / 429 (4.66%)
    11 / 213 (5.16%)
         occurrences all number
    21
    11
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    23 / 429 (5.36%)
    6 / 213 (2.82%)
         occurrences all number
    26
    9
    Hyperglycaemia
         subjects affected / exposed
    22 / 429 (5.13%)
    9 / 213 (4.23%)
         occurrences all number
    22
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 May 2020
    Changed study design to reflect remdesivir as background therapy; amended protocol to include only the presented study arms; updated eligibility criteria
    01 Jul 2020
    Clarified eligibility criteria
    21 Sep 2020
    Updated primary efficacy endpoint; updated eligibility criteria; increased sample size
    10 Dec 2020
    Updated wording of primary endpoint; updated secondary endpoints; updated sample size estimate
    22 Feb 2021
    Added secondary endpoints; updated 'time to event' 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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