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Evaluation of the Efficacy and Safety of Sarilumab in Hospitalized Patients With COVID-19

Sponsor
Regeneron Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT04315298
Collaborator
Sanofi (Industry)
1,912
Enrollment
62
Locations
6
Arms
5.5
Actual Duration (Months)
30.8
Patients Per Site
5.6
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Phase 2:

The primary objective of the study is to evaluate the clinical efficacy of sarilumab relative to the control arm in adult patients hospitalized with COVID-19 regardless of disease severity strata.

Phase 3 Cohort 1:

The primary objective of the study is to evaluate the clinical efficacy of sarilumab relative to the control arm in adult patients hospitalized with critical COVID-19 receiving mechanical ventilation at baseline.

Phase 3 Cohort 2:

The primary objective of the study is to evaluate the clinical efficacy of sarilumab relative to the control arm in adult patients hospitalized with COVID-19 receiving mechanical ventilation at baseline.

Condition or Disease Intervention/Treatment Phase
Phase 2/Phase 3

Detailed Description

Phase 2 and Phase 3 Cohort 1 completed. Cohorts 2 and 3 terminated early based on Phase 3 Cohort 1 results.

Study Design

Study Type:
Interventional
Actual Enrollment :
1912 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
An Adaptive Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study Assessing Efficacy and Safety of Sarilumab for Hospitalized Patients With COVID-19
Actual Study Start Date :
Mar 18, 2020
Actual Primary Completion Date :
Jul 24, 2020
Actual Study Completion Date :
Sep 2, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Sarilumab 200mg IV (P2)

Phase 2

Drug: Sarilumab
Single or multiple intravenous (IV) doses of sarilumab. Additional doses may be administered if the patient meets protocol defined criteria.
Other Names:
  • Kevzara®
  • REGN88
  • SAR153191

    • Drug: Placebo
    Single or multiple intravenous (IV) doses of placebo to match sarilumab administration
    Experimental: Sarilumab 200mg IV (P3:C1)

    Phase 3: Cohort 1

    Drug: Sarilumab
    Single or multiple intravenous (IV) doses of sarilumab. Additional doses may be administered if the patient meets protocol defined criteria.
    Other Names:
  • Kevzara®
  • REGN88
  • SAR153191

    • Drug: Placebo
    Single or multiple intravenous (IV) doses of placebo to match sarilumab administration
    Experimental: Sarilumab 400mg IV (P2)

    Phase 2

    Drug: Sarilumab
    Single or multiple intravenous (IV) doses of sarilumab. Additional doses may be administered if the patient meets protocol defined criteria.
    Other Names:
  • Kevzara®
  • REGN88
  • SAR153191

    • Drug: Placebo
    Single or multiple intravenous (IV) doses of placebo to match sarilumab administration
    Experimental: Sarilumab 400mg IV (P3:C1)

    Phase 3: Cohort 1

    Drug: Sarilumab
    Single or multiple intravenous (IV) doses of sarilumab. Additional doses may be administered if the patient meets protocol defined criteria.
    Other Names:
  • Kevzara®
  • REGN88
  • SAR153191

    • Drug: Placebo
    Single or multiple intravenous (IV) doses of placebo to match sarilumab administration
    Experimental: Sarilumab 800mg IV (P3:C2)

    Phase 3: Cohort 2

    Drug: Sarilumab
    Single or multiple intravenous (IV) doses of sarilumab. Additional doses may be administered if the patient meets protocol defined criteria.
    Other Names:
  • Kevzara®
  • REGN88
  • SAR153191

    • Drug: Placebo
    Single or multiple intravenous (IV) doses of placebo to match sarilumab administration
    Experimental: Sarilumab 800mg IV (P3: C3)

    Phase 3: Cohort 3

    Drug: Sarilumab
    Single or multiple intravenous (IV) doses of sarilumab. Additional doses may be administered if the patient meets protocol defined criteria.
    Other Names:
  • Kevzara®
  • REGN88
  • SAR153191

    • Drug: Placebo
    Single or multiple intravenous (IV) doses of placebo to match sarilumab administration

    Outcome Measures

    Primary Outcome Measures

    1. Percent Change From Baseline in CRP Levels at Day 4 in Participants With Serum IL-6 Level Greater Than the ULN (Phase 2) [Baseline and Day 4]

      Percent Change from Baseline in C-Reactive Protein (CRP) Levels at Day 4 in Participants with Serum Interleukin 6 (IL-6) Level Greater than the Upper Limit of Normal (ULN) Least Squares (LS) means estimate of percent change from baseline at Day 4 (raw scale) for each treatment group is based on the Analysis of Covariance (ANCOVA) model. It is defined as anti-log of the estimate of dependent variable minus 1, i.e., (exp[ln(CRP at day 4/Baseline CRP)]-1. Negative numbers imply improvement in CRP.

    2. Percentage of Participants With at Least a 1-point Improvement in Clinical Status From Baseline to Day 22 Using the 7-point Ordinal Scale in Participants With Critical COVID-19 Receiving Mechanical Ventilation at Baseline (Phase 3 Cohort 1) [Day 22]

      The ordinal scale is an assessment of the clinical status of a participant. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity

    3. Percentage of Participants With at Least 1-point Improvement in Clinical Status Using the 7-point Ordinal Scale in Participants With COVID-19 Receiving Mechanical Ventilation at Baseline (Phase 3 Cohort 2) [Day 22]

      The ordinal scale is an assessment of the clinical status of a participant The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity

    Secondary Outcome Measures

    1. Time to Improvement (2 Points) in Clinical Status Assessment in Severe or Critical Patients With Serum IL-6 Levels Greater Than the Upper Limit of Normal (Phase 2) [Up to Day 29]

      Time to improvement (2 points) in clinical status assessment on the 7-point ordinal scale in severe or critical participants with serum IL-6 levels greater than the upper limit of normal (ULN). The ordinal scale is an assessment of the clinical status of a patient. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity

    2. Time to Improvement (2 Points) in Clinical Status Assessment in Severe or Critical Patients With All Serum IL-6 Levels (Phase 2) [Up to Day 29]

      Time to improvement (2 points) in clinical status assessment on the 7-point ordinal scale in severe or critical participants with all serum IL-6 levels. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity

    3. Time to Resolution of Fever for at Least 48 Hours Without Antipyretics or Until Discharge, Whichever is Sooner, in Patients With Documented Fever at Baseline (Phase 2) [Up to Day 29]

      Time to resolution of fever for at least 48 hours without antipyretics or until discharge, whichever is sooner, in patients with documented fever ≥38°C (oral), ≥38.4°C (rectal or tympanic), or ≥37.6°C (temporal or axillary) at Baseline. Resolution of fever is defined as postbaseline body temperature <37.2°C (oral), or <37.6°C (rectal or tympanic) or <36.8°C (temporal or axillary).

    4. Time to Resolution of Fever for at Least 48 Hours Without Antipyretics by Clinical Severity (Phase 2) [Up to day 29]

      Resolution of fever is defined as body temperature <=36.8 C (axilla or temporal) or<= 37.2 C (oral) or <37.6 C (rectal or tympanic) for at least 48 hours without antipyretics or until discharge. Resolution of fever is defined only in participants with presence of fever at baseline.

    5. Time to Resolution of Fever for at Least 48 Hours Without Antipyretics or Until Discharge, Whichever is Sooner, by Baseline IL-6 Levels (Phase 2) [Up to Day 29]

      Resolution of fever is defined as body temperature <=36.8 C (axilla or temporal) or<= 37.2 C (oral) or <37.6 C (rectal or tympanic) for at least 48 hours without antipyretics or until discharge, by baseline IL-6 levels. Resolution of fever is defined only in participants with presence of fever at baseline.

    6. Time to Improvement in Oxygenation for at Least 48 Hours (Phase 2) [Up to day 29]

      Improvement in oxygenation defined as increase in SpO2/FiO2 of 50 or greater compared to the nadir SpO2/FiO2

    7. Time to Improvement in Oxygenation for at Least 48 Hours by Baseline IL-6 Levels (Phase 2) [Up to day 29]

      Time to Improvement defined as increase in SpO2/FiO2 of 50 or greater compared to the nadir SpO2/FiO2

    8. Time to Resolution of Fever and Improvement in Oxygenation for at Least 48 Hours (Phase 2) [Up to day 29]

      Resolution of fever defined as postbaseline body temperature <37.2°C (oral), or <37.6°C (rectal or tympanic) or <36.8°C (temporal or axillary) Improvement in oxygenation defined as increase in SpO2/FiO2 of 50 or greater compared to the nadir SpO2/FiO2

    9. Percentage of Participants in Each Clinical Status Category Using the 7-point Ordinal Scale up to Day 29 (Phase 2) [Days 1, 3, 5, 8, 11, 15 and 29]

      Percentage of participants in each clinical status category using the 7-point ordinal scale from Baseline (Day 1) up to Day 29. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity

    10. Time to Discharge or to a National Early Warning Score 2 (NEWS2) of ≤2 and Maintained for 24 Hours (Phase 2) [Up to day 29]

      NEWS2 was used to standardize assessment of acute-illness severity, track clinical condition of participants and to alert clinical teams to participant deterioration. NEWS2 score was based on 7 clinical parameters: respiration rate, oxygen saturation, supplemental oxygen, systolic blood pressure, pulse rate, level of consciousness, and temperature. A score of 0, 1, 2, and 3 was allocated to each parameter except supplemental oxygen (a score of 0 or 1 was allocated) and level of consciousness (a score of 0 or 3 was allocated), where 0 = normal health condition to 3 = worst health condition; higher score indicated more severity. All scores were summed to get an aggregate score. Aggregate NEWS2 score ranged from 0 to 19, with higher scores meaning more severity/higher risk: low risk (score 0 to 4); low to medium risk (score of 3 in any individual parameter); medium risk (score 5 to 6); high risk (score 7 to 19).

    11. Change From Baseline in NEWS2 Scoring System (Phase 2) [Days 3, 5, 8, 11, 15 and 29]

      NEWS2 was used to standardize assessment of acute-illness severity, track clinical condition of participants and to alert clinical teams to participant deterioration. NEWS2 score was based on 7 clinical parameters: respiration rate, oxygen saturation, supplemental oxygen, systolic blood pressure, pulse rate, level of consciousness, and temperature. A score of 0, 1, 2, and 3 was allocated to each parameter except supplemental oxygen (a score of 0 or 1 was allocated) and level of consciousness (a score of 0 or 3 was allocated), where 0 = normal health condition to 3 = worst health condition; higher score indicated more severity. All scores were summed to get an aggregate score. Aggregate NEWS2 score ranged from 0 to 19, with higher scores meaning more severity/higher risk: low risk (score 0 to 4); low to medium risk (score of 3 in any individual parameter); medium risk (score 5 to 6); high risk (score 7 to 19).

    12. Number of Days With Fever (Phase 2) [Up to Day 29]

      Defined as ≥38°C (oral), ≥38.4°C (rectal or tympanic) or ≥37.6°C (temporal or axillary)

    13. Percentage of Participants Alive, Off Oxygen (Phase 2) [At Day 29]

    14. Number of Days of Resting Respiratory Rate >24 Breaths/Min (Phase 2) [Up to day 29]

    15. Number of Days With Hypoxemia (Phase 2) [Up to day 29]

    16. Number of Days of Supplemental Oxygen Use (Phase 2) [Up to day 29]

    17. Time to Saturation ≥94% on Room Air (Phase 2) [Up to day 29]

    18. Number of Ventilator Free Days (Phase 2) [Up to Day 22]

      Summary of Ventilator-free days during study in Participants using Invasive Mechanical Ventilation at Baseline

    19. Number of Participants Who Initiated Mechanical Ventilation After Baseline (Phase 2) [Up to Day 29]

    20. Number of Days in an Intensive Care Unit (ICU) in Participants Who Were Not in ICU at Baseline (Phase 2) [Up to Day 29]

    21. Number of Days of Hospitalization Among Survivors (Phase 2) [Up to day 29]

    22. Number of Deaths Due to Any Cause [Up to day 60]

      Number of deaths due to any cause (All-Cause Mortality)

    23. Percentage of Participants With at Least 1-point Improvement in Clinical Status Using the 7-point Ordinal Scale in Participants With Critical COVID-19 (Phase 3 Cohort 1: Critical ITT) [Day 22]

      The ordinal scale is an assessment of the clinical status of a participant. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity

    24. Percentage of Participants Who Recover (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline) [Day 22]

      Percentage of Participants Who Recover (Discharged, or Alive without Supplemental Oxygen Use or at Pre-COVID Oxygen Use) at Day 22

    25. Percentage of Participants Who Recover (Phase 3 Cohort 1: Critical ITT) [Day 22]

      Percentage of Participants Who Recover (Discharged, or Alive without Supplemental Oxygen Use or at Pre-COVID Oxygen Use) at Day 22

    26. Percentage of Participants Who Die (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline) [Up to Day 29 and Day 60]

      Percentage of Participants who die through Day 29 and Day 60

    27. Percentage of Participants Who Die (Phase 3 Cohort 1: Critical ITT) [Up to Day 29 and Day 60]

      Percentage of Participants who die through Day 29 and Day 60

    28. Percentage of Participants Alive Not Receiving Mechanical Ventilation or ECMO at Day 22 (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline) [At Day 22]

      Percentage of participants alive not receiving mechanical ventilation or ECMO at Day 22 (Phase 3 Cohort 1)

    29. Percentage of Participants With at Least a 2-point Improvement in Clinical Status From Baseline to Day 22 Using the 7-point Ordinal Scale (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline) [At Day 22]

      Percentage of participants with at least a 2-point improvement in clinical status from baseline to Day 22 using the 7-point ordinal scale. The ordinal scale is an assessment of the clinical status of a participant. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity

    30. Percentage of Participants Alive Not Receiving Mechanical Ventilation or ECMO at Day 22 (Phase 3 Cohort 1: Critical ITT) [At Day 22]

      Percentage of participants alive not receiving mechanical ventilation or ECMO at Day 22 (Phase 3 Cohort 1)

    31. Percentage of Participants With at Least a 2-point Improvement in Clinical Status From Baseline to Day 22 Using the 7-point Ordinal Scale (Phase 3 Cohort 1: Critical ITT) [At Day 22]

      Percentage of participants with at least a 2-point improvement in clinical status from baseline to Day 22 using the 7-point ordinal scale. The ordinal scale is an assessment of the clinical status of a participant. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity

    32. Time to at Least 1-point Improvement in Clinical Status Assessment on the 7-point Ordinal Scale (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline) [Up to day 29]

      The ordinal scale is an assessment of the clinical status of a participant. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity

    33. Time to at Least 1-point Improvement in Clinical Status Assessment on the 7-point Ordinal Scale (Phase 3 Cohort 1: Critical ITT) [Up to day 29]

      The ordinal scale is an assessment of the clinical status of a participant. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity

    34. Time to at Least 1-point Improvement in Clinical Status Assessment on the 7-point Ordinal Scale (Phase 3 Cohort 2) [Up to day 29]

      The ordinal scale is an assessment of the clinical status of a participant. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity

    35. Time to at Least 2-point Improvement in Clinical Status Assessment on the 7-point Ordinal Scale (Phase 3 Cohort 1) [Up to day 29]

      The ordinal scale is an assessment of the clinical status of a participant. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity

    36. Time to at Least 2-point Improvement in Clinical Status Assessment on the 7-point Ordinal Scale (Phase 3 Cohort 1: Critical ITT) [Up to day 29]

      The ordinal scale is an assessment of the clinical status of a participant. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity

    37. Percentage of Participants Receiving Mechanical Ventilation or ECMO at Day 22 (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline) [Day 22]

    38. Percentage of Participants Receiving Mechanical Ventilation or ECMO at Day 22 (Phase 3 Cohort 1: Critical ITT) [Day 22]

    39. Percentage of Patients Discharged and Alive (Phase 3 Cohort 1) [At Day 22]

      Percentage of Patients Discharged and Alive at Day 22

    40. Percentage of Participants Discharged and Alive at Day 22 (Phase 3 Cohort 1: Critical ITT) [At Day 22]

      Percentage of Participants Discharged and Alive at Day 22

    41. Time to Recovery (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline) [Up to day 29]

      Phase 3 Cohort 1 Time to Recovery (Discharged, or Alive without Supplemental Oxygen Use or at Pre-COVID Oxygen Use)

    42. Time to Recovery (Phase 3 Cohort 1: Critical ITT) [Up to day 29]

      Phase 3 Cohort 1 Time to Recovery (Discharged, or Alive without Supplemental Oxygen Use or at Pre-COVID Oxygen Use)

    43. Time to Recovery (Phase 3 Cohort 2) [Up to day 29]

      Time to Recovery (Discharged, or Alive without Supplemental Oxygen Use or at Pre-COVID Oxygen Use)

    44. Time to Death (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline) [Up to day 60]

      Phase 3 Cohort 1 Time to Death (All-Cause Mortality)

    45. Time to Death (Phase 3 Cohort 1: Critical ITT) [Up to day 60]

      Time to Death (All-Cause Mortality)

    46. Time to Death (Phase 3 Cohort 2) [Up to day 60]

      Time to Death (All-Cause Mortality)

    47. Number of Ventilator-Free Days (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline) [Days 8, 15, 22 and 29]

      Number of Ventilator-Free days up to Day 29 (Phase 3 Cohort 1)

    48. Number of Ventilator-Free Days (Phase 3 Cohort 1: Critical ITT) [Days 8, 15, 22 and 29]

      Number of Ventilator-Free days up to Day 29 (Phase 3 Cohort 1)

    49. Number of Days of Hospitalization Among Survivors (Phase 3 Cohort 1) [Days 8, 15, 22 and 29]

      Number of days of hospitalization among survivors (Phase 3 Cohort 1)

    50. Number of Days of Hospitalization Among Survivors (Phase 3 Cohort 1: Critical ITT) [Days 8, 15, 22 and 29]

      Number of days of hospitalization among survivors (Phase 3 Cohort 1: Critical ITT population)

    51. Number of Participants With Any Serious Adverse Event [Up to day 60]

    52. Number of Participants With Grade 4 Neutropenia (ANC <500/mm3) [Up to day 60]

      Grade 4 Neutropenia defined as Absolute Neutrophil Count (ANC) of less than 500 per cubic millimeter(mm3)

    53. Number of Participants With Severe or Life-threatening Bacterial, Invasive Fungal, or Opportunistic Infection [Up to day 60]

    54. Number of Participants With Grade 4 Neutropenia and Concurrent Invasive Infection [Up to day 60]

    55. Number of Participants With Grade >=2 Infusion Related Reactions [Up to day 60]

    56. Number of Participants With Grade >=2 Hypersensitivity Reactions [Up to day 60]

    57. Number of Participants With Gastrointestinal Perforation [Up to day 60]

    58. Mean Observed Leukocyte Values Across Study Days (Phase 2) [Days 1, 4, 15 and 29]

    59. Mean Observed Leukocyte Values Across Study Days (Phase 3) [Days 1, 4, 15 and 29]

    60. Mean Observed Hemoglobin Values Across Study Days (Phase 2) [Days 1, 4, 15 and 29]

    61. Mean Observed Hemoglobin Values Across Study Days (Phase 3) [Days 1, 4, 15 and 29]

    62. Mean Observed Platelet Count Across Study Days (Phase 2) [Days 1, 4, 15 and 29]

    63. Mean Observed Platelet Count Across Study Days (Phase 3) [Days 1, 4, 15 and 29]

    64. Mean Observed Total Bilirubin Values Across Study Days (Phase 2) [Days 1, 4, 15 and 29]

    65. Mean Observed Total Bilirubin Across Study Days (Phase 3) [Days 1, 4, 15 and 29]

    66. Mean Observed Aspartate Aminotransferase Values Across Study Days (Phase 2) [Days 1, 4, 15 and 29]

    67. Mean Observed Aspartate Aminotransferase Values Across Study Days (Phase 3) [Days 1, 4, 15 and 29]

    68. Mean Observed Alanine Aminotransferase Values Across Study Days (Phase 2) [Days 1, 4, 15 and 29]

    69. Mean Observed Alanine Aminotransferase Values Across Study Days (Phase 3) [Days 1, 4, 15 and 29]

    70. Mean Observed Creatinine Values Across Study Days (Phase 2) [Days 1, 4, 15 and 29]

    71. Mean Observed Creatinine Values Across Study Days (Phase 3) [Days 1, 4, 15 and 29]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Key Inclusion Criteria:

    • Laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR), result from any specimen (or other commercial or public health assay) within 2 weeks prior to randomization and no alternative explanation for current clinical condition

    • Hospitalized with illness of any duration with evidence of pneumonia, requires supplemental oxygen and/or assisted ventilation and meets one of the following:

    • Phase 2 and Phase 3 Cohort 1:

    Meets 1 of the following criteria at baseline:

    • Severe disease OR

    • Critical disease OR

    • Multi-system organ dysfunction OR

    • Immunocompromised

    • Phase 3 Cohort 2:

    Patients must be receiving mechanical ventilation to treat respiratory failure due to COVID-19

    • Phase 3 Cohort 3:

    Patients must be receiving supplemental oxygen to treat hypoxemia delivered by one of the following devices:

    • Non-rebreather mask, OR

    • High-flow device with at least 50% FiO2, OR

    • Non-invasive positive pressure ventilator

    • Ability to provide informed consent signed by study patient or legally acceptable representative

    • Willingness and ability to comply with study-related procedures/assessments

    Key Exclusion Criteria:

    • In the opinion of the investigator, not expected to survive for more than 48 hours from screening

    • Presence of any of the following abnormal laboratory values at screening: absolute neutrophil count (ANC) less than 2000 mm3, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 x upper limit of normal (ULN), platelets <50,000 per mm3

    • Treatment with anti-IL 6, anti-IL-6R antagonists, or with Janus kinase inhibitors (JAKi) in the past 30 days or plans to receive during the study period

    • Current treatment with the simultaneous combination of leflunomide and methotrexate

    • Known active tuberculosis (TB), history of incompletely treated TB, suspected or known extrapulmonary TB, suspected or known systemic bacterial or fungal infections

    • Participation in a double-blind clinical research study evaluating an investigational product (IP) or therapy within 3 months and less than 5 half-lives of IP prior to the screening visit (The use of remdesivir, hydroxychloroquine, or other treatments being used for COVID-19 treatments in the context of an open-label study, Emergency Use Authorization (EUA), compassionate use protocol or open-label use is permitted)

    • Any physical examination findings, and/or history of any illness, concomitant medications or recent live vaccines that, in the opinion of the study investigator, might confound the results of the study or pose an additional risk to the patient by their participation in the study

    • Known systemic hypersensitivity to sarilumab or the excipients of the drug product

    • Phase 3 Cohort 2 and Cohort 3 only:

    • Known or suspected history of immunosuppression or immunodeficiency disorder

    • Patients who require renal replacement therapy for acute kidney injury at randomization or who required renal replacement therapy within 72 hours prior to randomization

    • Patients who have circulatory shock requiring vasopressors at randomization or within 24 hours prior to randomization

    • Use of extracorporeal life support (eg, ECMO) or, in the opinion of the investigator, there is a high likelihood that extracorporeal life support will be initiated within 48 hours after randomization

    NOTE: Other protocol defined inclusion / exclusion criteria may apply

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Regeneron Study Site Los Angeles California United States 90095
    2 Regeneron Study Site Sacramento California United States 95817
    3 Regeneron Study Site Santa Monica California United States 90404
    4 Regeneron Study Site Aurora Colorado United States 80045
    5 Regeneron Study Site Denver Colorado United States 80206
    6 Regeneron Study Site New Haven Connecticut United States 06520
    7 Regeneron Study Site Washington District of Columbia United States 20010
    8 Regeneron Study Site Gainesville Florida United States 32610
    9 Regeneron Study Site Orlando Florida United States 32803
    10 Regeneron Study Site Tampa Florida United States 33606
    11 Regeneron Study Site Atlanta Georgia United States 30322
    12 Regeneron Study Site Decatur Georgia United States 30033
    13 Regeneron Study Site Marietta Georgia United States 30060
    14 Regeneron Study Site Chicago Illinois United States 60611
    15 Regeneron Study Site Chicago Illinois United States 60612
    16 Regeneron Study Site New Orleans Louisiana United States 70112
    17 Regeneron Study Site Boston Massachusetts United States 02111
    18 Regeneron Study Site Boston Massachusetts United States 02114
    19 Regeneron Study Site Boston Massachusetts United States 02215
    20 Regeneron Study Site Ann Arbor Michigan United States 48109
    21 Regeneron Study Site Rochester Minnesota United States 55905
    22 Regeneron Study Site Edison New Jersey United States 08820
    23 Regeneron Study Site Hackensack New Jersey United States 07601
    24 Regeneron Study Site Livingston New Jersey United States 07039
    25 Regeneron Study Site Morristown New Jersey United States 07960
    26 Regeneron Study Site Neptune New Jersey United States 07753
    27 Regeneron Study Site Newark New Jersey United States 07112
    28 Regeneron Study Site Teaneck New Jersey United States 07666
    29 Regeneron Study Site Bronx New York United States 10451
    30 Regeneron Study Site 1 Bronx New York United States 10461
    31 Regeneron Study Site 2 Bronx New York United States 10461
    32 Regeneron Study Site Bronx New York United States 10467
    33 Regeneron Study Site Brooklyn New York United States 11219
    34 Regeneron Study Site Buffalo New York United States 14263
    35 Regeneron Study Site Elmhurst New York United States 11373
    36 Regeneron Study Site 1 Manhasset New York United States 11030
    37 Regeneron Study Site 2 Manhasset New York United States 11030
    38 Regeneron Study Site New York New York United States 10003
    39 Regeneron Study Site New York New York United States 10016
    40 Regeneron Study Site 1 New York New York United States 10025
    41 Regeneron Study Site 2 New York New York United States 10025
    42 Regeneron Study Site New York New York United States 10029
    43 Regeneron Study Site New York New York United States 10032
    44 Regeneron Study Site New York New York United States 10037
    45 Regeneron Study Site New York New York United States 10065
    46 Regeneron Study Site New York New York United States 10075
    47 Regeneron Study Site Stony Brook New York United States 11794
    48 Regeneron Study Site Valhalla New York United States 10595
    49 Regeneron Study Site Tulsa Oklahoma United States 74104
    50 Regeneron Study Site Portland Oregon United States 97213
    51 Regeneron Study Site Portland Oregon United States 97239
    52 Regeneron Study Site Danville Pennsylvania United States 17822
    53 Regeneron Study Site Philadelphia Pennsylvania United States 19140
    54 Regeneron Study Site Scranton Pennsylvania United States 18510
    55 Regeneron Study Site Wilkes-Barre Pennsylvania United States 18711
    56 Regeneron Study Site Dallas Texas United States 75246
    57 Regeneron Study Site Dallas Texas United States 75390
    58 Regeneron Study Site Murray Utah United States 84107
    59 Regeneron Study Site Falls Church Virginia United States 22042
    60 Regeneron Study Site Richmond Virginia United States 23298
    61 Regeneron Study Site Everett Washington United States 98201
    62 Regeneron Study Site Renton Washington United States 98055

    Sponsors and Collaborators

    • Regeneron Pharmaceuticals
    • Sanofi

    Investigators

    • Study Director: Clinical Trial Management, Regeneron Pharmaceuticals

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Regeneron Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT04315298
    Other Study ID Numbers:
    • 6R88-COV-2040
    First Posted:
    Mar 19, 2020
    Last Update Posted:
    Sep 23, 2021
    Last Verified:
    Sep 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Regeneron Pharmaceuticals
    COVID-19
    SARS-COV-2
    coronavirus
    IL-6
    sarilumab
    acute respiratory distress syndrome
    treatment
    Additional relevant MeSH terms:
    COVID-19

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail Of 1946 participants screened, 1912 were randomized and 1861 were treated. 51 randomized participants were never treated: 26 withdrew consent, 14 investigator decision, 9 deaths, and 3 other.
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical Phase 3 Cohort 1: Placebo - Severe Phase 3 Cohort 1: Sarilumab 200mg IV - Severe Phase 3 Cohort 1: Sarilumab 400mg IV - Severe Phase 3 Cohort 1: Placebo - MSOD Phase 3 Cohort 1: Sarilumab 200mg IV - MSOD Phase 3 Cohort 1: Sarilumab 400mg IV - MSOD Phase 3 Cohort 1: Placebo - Immunocompromised Phase 3 Cohort 1: Sarilumab 200mg IV - Immunocompromised Phase 3 Cohort 1: Sarilumab 400mg IV - Immunocompromised Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800mg IV Phase 3 Cohort 3: Placebo Phase 3 Cohort 3: Sarilumab 800mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline
    Period Title: Overall Study
    STARTED 90 187 180 170 242 338 70 140 137 46 95 92 8 12 15 15 16 6 2
    COMPLETED 61 117 125 101 157 209 52 111 101 29 53 51 5 8 9 9 13 5 2
    NOT COMPLETED 29 70 55 69 85 129 18 29 36 17 42 41 3 4 6 6 3 1 0

    Baseline Characteristics

    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical Phase 3 Cohort 1: Placebo - Severe Phase 3 Cohort 1: Sarilumab 200mg IV - Severe Phase 3 Cohort 1 :Sarilumab 400mg IV - Severe Phase 3 Cohort 1: Placebo - MSOD Phase 3 Cohort 1: Sarilumab 200mg IV - MSOD Phase 3 Cohort 1: Sarilumab 400mg IV - MSOD Phase 3 Cohort 1: Placebo - Immunocompromised Phase 3 Cohort 1: Sarilumab 200mg IV - Immunocompromised Phase 3 Cohort 1: Sarilumab 400mg IV - Immunocompromised Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800mg IV Phase 3 Cohort 3: Placebo Phase 3 Cohort 3: Sarilumab 800mg IV Total
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline Total of all reporting groups
    Overall Participants 90 187 180 170 242 338 70 140 137 46 95 92 8 12 15 15 16 6 2 1861
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    60.3
    (13.4)
    57.1
    (14.6)
    56.3
    (14.7)
    60.1
    (15.0)
    58.5
    (13.7)
    61.8
    (14.2)
    61.2
    (13.9)
    61.3
    (15.1)
    62.2
    (15.3)
    59.9
    (13.7)
    59.1
    (12.4)
    61.1
    (15.1)
    58.3
    (11.9)
    57.7
    (7.0)
    65.2
    (8.0)
    48.6
    (15.3)
    52.9
    (14.7)
    61.5
    (9.1)
    66.0
    (7.1)
    59.7
    (14.4)
    Sex: Female, Male (Count of Participants)
    Female
    21
    23.3%
    63
    33.7%
    42
    23.3%
    59
    34.7%
    67
    27.7%
    111
    32.8%
    25
    35.7%
    59
    42.1%
    51
    37.2%
    21
    45.7%
    41
    43.2%
    34
    37%
    4
    50%
    3
    25%
    4
    26.7%
    4
    26.7%
    5
    31.3%
    3
    50%
    0
    0%
    617
    33.2%
    Male
    69
    76.7%
    124
    66.3%
    138
    76.7%
    111
    65.3%
    175
    72.3%
    227
    67.2%
    45
    64.3%
    81
    57.9%
    86
    62.8%
    25
    54.3%
    54
    56.8%
    58
    63%
    4
    50%
    9
    75%
    11
    73.3%
    11
    73.3%
    11
    68.8%
    3
    50%
    2
    100%
    1244
    66.8%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    16
    17.8%
    54
    28.9%
    40
    22.2%
    59
    34.7%
    77
    31.8%
    115
    34%
    19
    27.1%
    30
    21.4%
    30
    21.9%
    12
    26.1%
    27
    28.4%
    21
    22.8%
    1
    12.5%
    3
    25%
    4
    26.7%
    5
    33.3%
    10
    62.5%
    2
    33.3%
    1
    50%
    526
    28.3%
    Not Hispanic or Latino
    59
    65.6%
    98
    52.4%
    105
    58.3%
    87
    51.2%
    119
    49.2%
    163
    48.2%
    40
    57.1%
    80
    57.1%
    88
    64.2%
    26
    56.5%
    46
    48.4%
    47
    51.1%
    5
    62.5%
    7
    58.3%
    10
    66.7%
    5
    33.3%
    6
    37.5%
    3
    50%
    0
    0%
    994
    53.4%
    Unknown or Not Reported
    15
    16.7%
    35
    18.7%
    35
    19.4%
    24
    14.1%
    46
    19%
    60
    17.8%
    11
    15.7%
    30
    21.4%
    19
    13.9%
    8
    17.4%
    22
    23.2%
    24
    26.1%
    2
    25%
    2
    16.7%
    1
    6.7%
    5
    33.3%
    0
    0%
    1
    16.7%
    1
    50%
    341
    18.3%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    1
    0.6%
    1
    0.4%
    1
    0.3%
    0
    0%
    2
    1.4%
    0
    0%
    1
    2.2%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    6
    0.3%
    Asian
    9
    10%
    20
    10.7%
    21
    11.7%
    13
    7.6%
    10
    4.1%
    8
    2.4%
    2
    2.9%
    6
    4.3%
    13
    9.5%
    5
    10.9%
    3
    3.2%
    2
    2.2%
    0
    0%
    1
    8.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    113
    6.1%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    1
    0.6%
    0
    0%
    1
    0.4%
    0
    0%
    1
    1.4%
    1
    0.7%
    1
    0.7%
    0
    0%
    0
    0%
    1
    1.1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    6
    0.3%
    Black or African American
    15
    16.7%
    32
    17.1%
    31
    17.2%
    23
    13.5%
    39
    16.1%
    65
    19.2%
    10
    14.3%
    35
    25%
    25
    18.2%
    8
    17.4%
    23
    24.2%
    23
    25%
    2
    25%
    2
    16.7%
    9
    60%
    3
    20%
    3
    18.8%
    2
    33.3%
    0
    0%
    350
    18.8%
    White
    39
    43.3%
    70
    37.4%
    64
    35.6%
    74
    43.5%
    89
    36.8%
    127
    37.6%
    28
    40%
    45
    32.1%
    49
    35.8%
    11
    23.9%
    29
    30.5%
    25
    27.2%
    3
    37.5%
    3
    25%
    3
    20%
    7
    46.7%
    8
    50%
    2
    33.3%
    1
    50%
    677
    36.4%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    27
    30%
    65
    34.8%
    63
    35%
    59
    34.7%
    102
    42.1%
    137
    40.5%
    29
    41.4%
    51
    36.4%
    49
    35.8%
    21
    45.7%
    40
    42.1%
    41
    44.6%
    3
    37.5%
    6
    50%
    3
    20%
    5
    33.3%
    5
    31.3%
    2
    33.3%
    1
    50%
    709
    38.1%
    CRP levels (milligrams per Liter (mg/L)) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [milligrams per Liter (mg/L)]
    192.537
    (122.295)
    191.997
    (124.583)
    195.037
    (119.274)
    167.476
    (115.020)
    187.573
    (108.085)
    179.085
    (103.837)
    111.933
    (81.789)
    127.811
    (116.058)
    129.355
    (136.734)
    205.978
    (118.459)
    235.395
    (280.665)
    232.924
    (128.435)
    141.207
    (71.915)
    203.356
    (118.998)
    185.740
    (91.237)
    226.846
    (112.047)
    212.920
    (107.702)
    177.334
    (79.490)
    258.081
    (200.704)
    180.010
    (131.909)

    Outcome Measures

    1. Primary Outcome
    Title Percent Change From Baseline in CRP Levels at Day 4 in Participants With Serum IL-6 Level Greater Than the ULN (Phase 2)
    Description Percent Change from Baseline in C-Reactive Protein (CRP) Levels at Day 4 in Participants with Serum Interleukin 6 (IL-6) Level Greater than the Upper Limit of Normal (ULN) Least Squares (LS) means estimate of percent change from baseline at Day 4 (raw scale) for each treatment group is based on the Analysis of Covariance (ANCOVA) model. It is defined as anti-log of the estimate of dependent variable minus 1, i.e., (exp[ln(CRP at day 4/Baseline CRP)]-1. Negative numbers imply improvement in CRP.
    Time Frame Baseline and Day 4

    Outcome Measure Data

    Analysis Population Description
    Phase 2 mITT population: The modified intention-to-treat (mITT) population includes all randomized participants who received at least one dose of the study drug and have high baseline IL-6 levels.
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 80 152 153
    Least Squares Mean (Standard Error) [Percent Change]
    -0.20
    (0.077)
    -0.77
    (0.018)
    -0.78
    (0.017)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments P-value is based on the ANCOVA model for differences between treatment groups in terms of [ln(CRP at day 4 ) - ln(baseline CRP)].
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean (log scale)
    Estimated Value -1.25
    Confidence Interval (2-Sided) 95%
    -1.456 to -1.035
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.107
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments p-value is based on the ANCOVA model for differences between treatment groups in terms of [ln(CRP at day 4 ) - ln(baseline CRP)].
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean (log scale)
    Estimated Value -1.30
    Confidence Interval (2-Sided) 95%
    -1.511 to -1.090
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.107
    Estimation Comments
    2. Primary Outcome
    Title Percentage of Participants With at Least a 1-point Improvement in Clinical Status From Baseline to Day 22 Using the 7-point Ordinal Scale in Participants With Critical COVID-19 Receiving Mechanical Ventilation at Baseline (Phase 3 Cohort 1)
    Description The ordinal scale is an assessment of the clinical status of a participant. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity
    Time Frame Day 22

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1 Intention-to-treat (ITT) participants with a disease severity of critical and mechanical ventilation at baseline.
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 62 104 132
    Number (95% Confidence Interval) [Percentage of participants]
    35.5
    39.4%
    43.3
    23.2%
    43.2
    24%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3707
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 7.1
    Confidence Interval (2-Sided) 95%
    -8.4 to 21.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3261
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 7.5
    Confidence Interval (2-Sided) 95%
    -7.4 to 21.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Primary Outcome
    Title Percentage of Participants With at Least 1-point Improvement in Clinical Status Using the 7-point Ordinal Scale in Participants With COVID-19 Receiving Mechanical Ventilation at Baseline (Phase 3 Cohort 2)
    Description The ordinal scale is an assessment of the clinical status of a participant The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity
    Time Frame Day 22

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 2 ITT participants receiving mechanical ventilation at baseline
    Arm/Group Title Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19
    Measure Participants 15 16
    Number (95% Confidence Interval) [Percentage of participants]
    60.0
    66.7%
    68.8
    36.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7328
    Comments
    Method Cochran-Mantel-Haenszel
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 6.2
    Confidence Interval (2-Sided) 95%
    -26.2 to 36.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Time to Improvement (2 Points) in Clinical Status Assessment in Severe or Critical Patients With Serum IL-6 Levels Greater Than the Upper Limit of Normal (Phase 2)
    Description Time to improvement (2 points) in clinical status assessment on the 7-point ordinal scale in severe or critical participants with serum IL-6 levels greater than the upper limit of normal (ULN). The ordinal scale is an assessment of the clinical status of a patient. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity
    Time Frame Up to Day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 mITT population: The modified intention-to-treat (mITT) population includes all randomized participants who received at least one dose of the study drug and have high baseline IL-6 levels.
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 62 117 120
    Median (95% Confidence Interval) [Days]
    16.0
    15.0
    14.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5687
    Comments P-value based on log-rank test stratified by disease severity (severe, critical) and use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.12
    Confidence Interval (2-Sided) 95%
    0.76 to 1.66
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7014
    Comments P-value based on log-rank test stratified by disease severity (severe, critical) and use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.09
    Confidence Interval (2-Sided) 95%
    0.74 to 1.62
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    Title Time to Improvement (2 Points) in Clinical Status Assessment in Severe or Critical Patients With All Serum IL-6 Levels (Phase 2)
    Description Time to improvement (2 points) in clinical status assessment on the 7-point ordinal scale in severe or critical participants with all serum IL-6 levels. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity
    Time Frame Up to Day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 Severe and Critical ITT population. The intention-to-treat (ITT) population includes all randomized patients who received at least one dose of the study drug.
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 69 144 139
    Median (95% Confidence Interval) [Days]
    15.0
    14.0
    13.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3622
    Comments P-value based on log-rank test stratified by disease severity (severe, critical) and use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.18
    Confidence Interval (2-Sided) 95%
    0.83 to 1.70
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5802
    Comments P-value based on log-rank test stratified by disease severity (severe, critical) and use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.13
    Confidence Interval (2-Sided) 95%
    0.79 to 1.63
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    6. Secondary Outcome
    Title Time to Resolution of Fever for at Least 48 Hours Without Antipyretics or Until Discharge, Whichever is Sooner, in Patients With Documented Fever at Baseline (Phase 2)
    Description Time to resolution of fever for at least 48 hours without antipyretics or until discharge, whichever is sooner, in patients with documented fever ≥38°C (oral), ≥38.4°C (rectal or tympanic), or ≥37.6°C (temporal or axillary) at Baseline. Resolution of fever is defined as postbaseline body temperature <37.2°C (oral), or <37.6°C (rectal or tympanic) or <36.8°C (temporal or axillary).
    Time Frame Up to Day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 ITT population with presence of fever at baseline
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 50 114 117
    Median (95% Confidence Interval) [Days]
    17.0
    18.0
    18.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2340
    Comments P-value based on log-rank test stratified by disease severity (severe, critical and MSOD) and use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.29
    Confidence Interval (2-Sided) 95%
    0.83 to 2.02
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6949
    Comments P-value based on log-rank test stratified by disease severity (severe, critical and MSOD) and use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.15
    Confidence Interval (2-Sided) 95%
    0.74 to 1.79
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    7. Secondary Outcome
    Title Time to Resolution of Fever for at Least 48 Hours Without Antipyretics by Clinical Severity (Phase 2)
    Description Resolution of fever is defined as body temperature <=36.8 C (axilla or temporal) or<= 37.2 C (oral) or <37.6 C (rectal or tympanic) for at least 48 hours without antipyretics or until discharge. Resolution of fever is defined only in participants with presence of fever at baseline.
    Time Frame Up to day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 ITT population with presence of fever at baseline
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 50 114 117
    Disease Severity: Severe
    7.0
    5.0
    6.0
    Disease Severity: Critical
    NA
    29.0
    20.5
    Disease Severity: Multisystem Organ Dysfunction
    NA
    NA
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: Severe
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3151
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.27
    Confidence Interval (2-Sided) 95%
    0.66 to 2.43
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: Severe
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1884
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.74
    Confidence Interval (2-Sided) 95%
    0.39 to 1.41
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: Critical
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4356
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.61
    Confidence Interval (2-Sided) 95%
    0.76 to 3.40
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: Critical
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0371
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 2.10
    Confidence Interval (2-Sided) 95%
    1.01 to 4.40
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: MSOD
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8923
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.98
    Confidence Interval (2-Sided) 95%
    0.32 to 3.05
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: MSOD
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6940
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.83
    Confidence Interval (2-Sided) 95%
    0.25 to 2.71
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    8. Secondary Outcome
    Title Time to Resolution of Fever for at Least 48 Hours Without Antipyretics or Until Discharge, Whichever is Sooner, by Baseline IL-6 Levels (Phase 2)
    Description Resolution of fever is defined as body temperature <=36.8 C (axilla or temporal) or<= 37.2 C (oral) or <37.6 C (rectal or tympanic) for at least 48 hours without antipyretics or until discharge, by baseline IL-6 levels. Resolution of fever is defined only in participants with presence of fever at baseline.
    Time Frame Up to Day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 ITT population with presence of fever and IL-6 measurement reported at baseline
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 48 102 104
    Disease Severity: Severe Baseline IL-6 < 87.04 picograms per milliliter (pg/mL) Median
    8.5
    5.0
    5.0
    Disease Severity: Severe Baseline IL-6 >= 87.04pg/mL (Median)
    5.0
    8.0
    NA
    Disease Severity: Critical Baseline IL-6 < 166.68pg/mL (Median)
    14.0
    16.5
    17.0
    Disease Severity: Critical Baseline IL-6 >= 166.68pg/mL (Median)
    NA
    NA
    25.0
    Disease Severity: MSOD Baseline IL-6 <254.95 pg/mL (Median)
    NA
    NA
    NA
    Disease Severity: MSOD Baseline IL-6 >= 254.95 pg/mL (Median)
    NA
    NA
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: Severe Baseline IL-6 < 87.04 pg/mL (median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0832
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 2.14
    Confidence Interval (2-Sided) 95%
    0.81 to 5.65
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: Severe Baseline IL-6 < 87.04 pg/mL (median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1369
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.93
    Confidence Interval (2-Sided) 95%
    0.77 to 4.80
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: Severe Baseline IL-6 >= 87.04 pg/mL (median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9636
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.74
    Confidence Interval (2-Sided) 95%
    0.28 to 1.95
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: Severe Baseline IL-6 >= 87.04 pg/mL (median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0038
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.24
    Confidence Interval (2-Sided) 95%
    0.08 to 0.74
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: Critical Baseline IL-6 < 166.68pg/mL (Median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7380
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.21
    Confidence Interval (2-Sided) 95%
    0.47 to 3.13
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: Critical Baseline IL-6 <166.68pg/mL (Median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7342
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.21
    Confidence Interval (2-Sided) 95%
    0.48 to 3.05
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: Critical Baseline IL-6 >= 166.68pg/mL (Median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1934
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 3.58
    Confidence Interval (2-Sided) 95%
    0.79 to 16.17
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: Critical Baseline IL-6 >= 166.68pg/mL (Median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0159
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 5.33
    Confidence Interval (2-Sided) 95%
    1.19 to 23.94
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: MSOD Baseline IL-6 <254.95 pg/mL (Median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6281
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.05
    Confidence Interval (2-Sided) 95%
    0.13 to 8.75
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: MSOD Baseline IL-6 <254.95 pg/mL (Median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4971
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.62
    Confidence Interval (2-Sided) 95%
    0.06 to 6.13
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: MSOD Baseline IL-6 >= 254.95 pg/mL (Median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2990
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.30
    Confidence Interval (2-Sided) 95%
    0.03 to 2.86
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: MSOD Baseline IL-6 >= 254.95 pg/mL (Median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9360
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.99
    Confidence Interval (2-Sided) 95%
    0.22 to 4.41
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    9. Secondary Outcome
    Title Time to Improvement in Oxygenation for at Least 48 Hours (Phase 2)
    Description Improvement in oxygenation defined as increase in SpO2/FiO2 of 50 or greater compared to the nadir SpO2/FiO2
    Time Frame Up to day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 ITT population
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 90 187 180
    Disease Severity: Severe
    7.0
    6.0
    11.0
    Disease Severity: Critical
    10.5
    20.0
    11.0
    Disease Severity: MSOD
    20.0
    NA
    19.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: Severe
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9032
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.87
    Confidence Interval (2-Sided) 95%
    0.52 to 1.47
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: Severe
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0052
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.50
    Confidence Interval (2-Sided) 95%
    0.29 to 0.88
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: Critical
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1168
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.76
    Confidence Interval (2-Sided) 95%
    0.48 to 1.21
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: Critical
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3753
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.09
    Confidence Interval (2-Sided) 95%
    0.69 to 1.72
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: MSOD
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4956
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.81
    Confidence Interval (2-Sided) 95%
    0.40 to 1.66
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: MSOD
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8439
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Cox Proportional Hazard
    Estimated Value 1.01
    Confidence Interval (2-Sided) 95%
    0.50 to 2.02
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    10. Secondary Outcome
    Title Time to Improvement in Oxygenation for at Least 48 Hours by Baseline IL-6 Levels (Phase 2)
    Description Time to Improvement defined as increase in SpO2/FiO2 of 50 or greater compared to the nadir SpO2/FiO2
    Time Frame Up to day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 ITT population with IL-6 measurement reported at baseline
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 82 167 160
    Severe Participants Baseline IL-6 < 67.11pg/mL (median)
    8.0
    5.0
    7.5
    Severe Participants Baseline IL-6 >= 67.11pg/mL (median)
    6.5
    8.5
    NA
    Critical Participants Baseline IL-6 < 131.90pg/mL (median)
    7.0
    17.0
    8.5
    Critical Participants Baseline IL-6 >= 131.90pg/mL (median)
    15.0
    NA
    14.0
    MSOD / Immunocompromised Participants Baseline IL-6 < 254.95pg/mL (median)
    14.0
    NA
    24.0
    MSOD / Immunocompromised Participants Baseline IL-6 >= 254.95pg/mL (median)
    24.0
    NA
    19.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: Severe Baseline IL-6 < 67.11 pg/mL (median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3890
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.21
    Confidence Interval (2-Sided) 95%
    0.52 to 2.79
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: Severe Baseline IL-6 >= 67.11pg/mL (median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7838
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.65
    Confidence Interval () 95%
    0.30 to 1.41
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: Severe Baseline IL-6 < 67.11 pg/mL (median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2370
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.68
    Confidence Interval (2-Sided) 95%
    0.28 to 1.65
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: Severe Baseline IL-6 >= 67.11pg/mL (median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0004
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.25
    Confidence Interval () 95%
    0.10 to 0.59
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: Critical Baseline IL-6 < 131.90 pg/mL (median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1740
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.70
    Confidence Interval (2-Sided) 95%
    0.37 to 1.32
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: Critical Baseline IL-6 >= 131.90 pg/mL (median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3664
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.80
    Confidence Interval (2-Sided) 95%
    0.38 to 1.66
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: Critical Baseline IL-6 < 131.90 pg/mL (median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7318
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.00
    Confidence Interval (2-Sided) 95%
    0.53 to 1.87
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: Critical Baseline IL-6 >= 131.90 pg/mL (median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4155
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.18
    Confidence Interval (2-Sided) 95%
    0.59 to 2.37
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: MSOD Baseline IL-6 < 254.95 pg/mL (median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6262
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.75
    Confidence Interval (2-Sided) 95%
    0.23 to 2.45
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: MSOD Baseline IL-6 >= 254.95 pg/mL (median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5530
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.70
    Confidence Interval () 95%
    0.21 to 2.30
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: MSOD Baseline IL-6 < 254.95 pg/mL (median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8775
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.85
    Confidence Interval (2-Sided) 95%
    0.25 to 2.85
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: MSOD Baseline IL-6 >= 254.95 pg/mL (median)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7485
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.10
    Confidence Interval (2-Sided) 95%
    0.41 to 2.99
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    11. Secondary Outcome
    Title Time to Resolution of Fever and Improvement in Oxygenation for at Least 48 Hours (Phase 2)
    Description Resolution of fever defined as postbaseline body temperature <37.2°C (oral), or <37.6°C (rectal or tympanic) or <36.8°C (temporal or axillary) Improvement in oxygenation defined as increase in SpO2/FiO2 of 50 or greater compared to the nadir SpO2/FiO2
    Time Frame Up to day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 ITT population
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 90 187 180
    Disease Severity: Severe
    7.0
    4.0
    6.0
    Disease Severity: Critical
    15.0
    22.0
    8.5
    Disease Severity: MSOD
    20.0
    NA
    24.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: Severe
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4556
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.06
    Confidence Interval (2-Sided) 95%
    0.63 to 1.79
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: Severe
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0248
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.60
    Confidence Interval (2-Sided) 95%
    0.35 to 1.04
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: Critical
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6842
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.02
    Confidence Interval (2-Sided) 95%
    0.62 to 1.67
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: Critical
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0671
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.43
    Confidence Interval (2-Sided) 95%
    0.89 to 2.32
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: MSOD
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6146
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.85
    Confidence Interval (2-Sided) 95%
    0.41 to 1.74
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: MSOD
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9730
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.98
    Confidence Interval (2-Sided) 95%
    0.48 to 1.99
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    12. Secondary Outcome
    Title Percentage of Participants in Each Clinical Status Category Using the 7-point Ordinal Scale up to Day 29 (Phase 2)
    Description Percentage of participants in each clinical status category using the 7-point ordinal scale from Baseline (Day 1) up to Day 29. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity
    Time Frame Days 1, 3, 5, 8, 11, 15 and 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 ITT population
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 90 187 180
    Disease Severity: Severe Day 1 Ordinal Scale = 1
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: Severe Day 1 Ordinal Scale = 2
    0
    0%
    0
    0%
    7.8
    4.3%
    Disease Severity: Severe Day 1 Ordinal Scale = 3
    0
    0%
    2.0
    1.1%
    3.9
    2.2%
    Disease Severity: Severe Day 1 Ordinal Scale = 4
    100
    111.1%
    94.0
    50.3%
    88.2
    49%
    Disease Severity: Severe Day 1 Ordinal Scale = 5
    0
    0%
    4.0
    2.1%
    0
    0%
    Disease Severity: Severe Day 1 Ordinal Scale = 6
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: Severe Day 1 Ordinal Scale = 7
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: Severe Day 3 Ordinal Scale = 1
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: Severe Day 3 Ordinal Scale = 2
    0
    0%
    4.0
    2.1%
    13.7
    7.6%
    Disease Severity: Severe Day 3 Ordinal Scale = 3
    4.0
    4.4%
    6.0
    3.2%
    5.9
    3.3%
    Disease Severity: Severe Day 3 Ordinal Scale = 4
    96.0
    106.7%
    88.0
    47.1%
    72.5
    40.3%
    Disease Severity: Severe Day 3 Ordinal Scale = 5
    0
    0%
    2.0
    1.1%
    3.9
    2.2%
    Disease Severity: Severe Day 3 Ordinal Scale = 6
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: Severe Day 3 Ordinal Scale = 7
    0
    0%
    0
    0%
    3.9
    2.2%
    Disease Severity: Severe Day 5 Ordinal Scale = 1
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: Severe Day 5 Ordinal Scale = 2
    8.0
    8.9%
    6.0
    3.2%
    21.6
    12%
    Disease Severity: Severe Day 5 Ordinal Scale = 3
    0
    0%
    8.0
    4.3%
    3.9
    2.2%
    Disease Severity: Severe Day 5 Ordinal Scale = 4
    72.0
    80%
    66.0
    35.3%
    49.0
    27.2%
    Disease Severity: Severe Day 5 Ordinal Scale = 5
    0
    0%
    4.0
    2.1%
    11.8
    6.6%
    Disease Severity: Severe Day 5 Ordinal Scale = 6
    4.0
    4.4%
    2.0
    1.1%
    2.0
    1.1%
    Disease Severity: Severe Day 5 Ordinal Scale = 7
    16.0
    17.8%
    14.0
    7.5%
    11.8
    6.6%
    Disease Severity: Severe Day 8 Ordinal Scale = 1
    0
    0%
    2.0
    1.1%
    0
    0%
    Disease Severity: Severe Day 8 Ordinal Scale = 2
    8.0
    8.9%
    4.0
    2.1%
    19.6
    10.9%
    Disease Severity: Severe Day 8 Ordinal Scale = 3
    4.0
    4.4%
    8.0
    4.3%
    5.9
    3.3%
    Disease Severity: Severe Day 8 Ordinal Scale = 4
    48.0
    53.3%
    34.0
    18.2%
    29.4
    16.3%
    Disease Severity: Severe Day 8 Ordinal Scale = 5
    0
    0%
    6.0
    3.2%
    2.0
    1.1%
    Disease Severity: Severe Day 8 Ordinal Scale = 6
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: Severe Day 8 Ordinal Scale = 7
    40.0
    44.4%
    46.0
    24.6%
    43.1
    23.9%
    Disease Severity: Severe Day 11 Ordinal Scale = 1
    0
    0%
    2.0
    1.1%
    11.8
    6.6%
    Disease Severity: Severe Day 11 Ordinal Scale = 2
    8.0
    8.9%
    4.0
    2.1%
    11.8
    6.6%
    Disease Severity: Severe Day 11 Ordinal Scale = 3
    0
    0%
    6.0
    3.2%
    3.9
    2.2%
    Disease Severity: Severe Day 11 Ordinal Scale = 4
    32.0
    35.6%
    14.0
    7.5%
    9.8
    5.4%
    Disease Severity: Severe Day 11 Ordinal Scale = 5
    4.0
    4.4%
    0
    0%
    2.0
    1.1%
    Disease Severity: Severe Day 11 Ordinal Scale = 6
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: Severe Day 11 Ordinal Scale = 7
    56.0
    62.2%
    74.0
    39.6%
    60.8
    33.8%
    Disease Severity: Severe Day 15 Ordinal Scale = 1
    0
    0%
    4.0
    2.1%
    15.7
    8.7%
    Disease Severity: Severe Day 15 Ordinal Scale = 2
    4.0
    4.4%
    2.0
    1.1%
    9.8
    5.4%
    Disease Severity: Severe Day 15 Ordinal Scale = 3
    0
    0%
    2.0
    1.1%
    0
    0%
    Disease Severity: Severe Day 15 Ordinal Scale = 4
    16.0
    17.8%
    6.0
    3.2%
    5.9
    3.3%
    Disease Severity: Severe Day 15 Ordinal Scale = 5
    4.0
    4.4%
    0
    0%
    0
    0%
    Disease Severity: Severe Day 15 Ordinal Scale = 6
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: Severe Day 15 Ordinal Scale = 7
    76.0
    84.4%
    86.0
    46%
    68.6
    38.1%
    Disease Severity: Severe Day 29 Ordinal Scale = 1
    0
    0%
    4.0
    2.1%
    17.6
    9.8%
    Disease Severity: Severe Day 29 Ordinal Scale = 2
    0
    0%
    2.0
    1.1%
    7.8
    4.3%
    Disease Severity: Severe Day 29 Ordinal Scale = 3
    0
    0%
    0
    0%
    2.0
    1.1%
    Disease Severity: Severe Day 29 Ordinal Scale = 4
    8.0
    8.9%
    2.0
    1.1%
    2.0
    1.1%
    Disease Severity: Severe Day 29 Ordinal Scale = 5
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: Severe Day 29 Ordinal Scale = 6
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: Severe Day 29 Ordinal Scale = 7
    92.0
    102.2%
    92.0
    49.2%
    70.6
    39.2%
    Disease Severity: Critical Day 1 Ordinal Scale = 1
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: Critical Day 1 Ordinal Scale = 2
    40.9
    45.4%
    64.9
    34.7%
    54.5
    30.3%
    Disease Severity: Critical Day 1 Ordinal Scale = 3
    9.1
    10.1%
    6.4
    3.4%
    6.8
    3.8%
    Disease Severity: Critical Day 1 Ordinal Scale = 4
    50.0
    55.6%
    28.7
    15.3%
    38.6
    21.4%
    Disease Severity: Critical Day 1 Ordinal Scale = 5
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: Critical Day 1 Ordinal Scale = 6
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: Critical Day 1 Ordinal Scale = 7
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: Critical Day 3 Ordinal Scale = 1
    0
    0%
    3.2
    1.7%
    1.1
    0.6%
    Disease Severity: Critical Day 3 Ordinal Scale = 2
    59.1
    65.7%
    71.3
    38.1%
    56.8
    31.6%
    Disease Severity: Critical Day 3 Ordinal Scale = 3
    9.1
    10.1%
    6.4
    3.4%
    10.2
    5.7%
    Disease Severity: Critical Day 3 Ordinal Scale = 4
    31.8
    35.3%
    19.1
    10.2%
    28.4
    15.8%
    Disease Severity: Critical Day 3 Ordinal Scale = 5
    0
    0%
    0
    0%
    1.1
    0.6%
    Disease Severity: Critical Day 3 Ordinal Scale = 6
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: Critical Day 3 Ordinal Scale = 7
    0
    0%
    0
    0%
    1.1
    0.6%
    Disease Severity: Critical Day 3 Ordinal Scale = Missing
    4.8
    5.3%
    0
    0%
    0
    0%
    Disease Severity: Critical Day 5 Ordinal Scale = 1
    0
    0%
    9.6
    5.1%
    4.5
    2.5%
    Disease Severity: Critical Day 5 Ordinal Scale = 2
    52.3
    58.1%
    64.9
    34.7%
    53.4
    29.7%
    Disease Severity: Critical Day 5 Ordinal Scale = 3
    11.4
    12.7%
    8.5
    4.5%
    9.1
    5.1%
    Disease Severity: Critical Day 5 Ordinal Scale = 4
    34.1
    37.9%
    14.9
    8%
    28.4
    15.8%
    Disease Severity: Critical Day 5 Ordinal Scale = 5
    2.3
    2.6%
    0
    0%
    2.3
    1.3%
    Disease Severity: Critical Day 5 Ordinal Scale = 6
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: Critical Day 5 Ordinal Scale = 7
    0
    0%
    2.1
    1.1%
    2.3
    1.3%
    Disease Severity: Critical Day 8 Ordinal Scale = 1
    6.8
    7.6%
    20.2
    10.8%
    9.1
    5.1%
    Disease Severity: Critical Day 8 Ordinal Scale = 2
    43.2
    48%
    50.0
    26.7%
    46.6
    25.9%
    Disease Severity: Critical Day 8 Ordinal Scale = 3
    6.8
    7.6%
    5.3
    2.8%
    1.1
    0.6%
    Disease Severity: Critical Day 8 Ordinal Scale = 4
    29.5
    32.8%
    16.0
    8.6%
    27.3
    15.2%
    Disease Severity: Critical Day 8 Ordinal Scale = 5
    0
    0%
    1.1
    0.6%
    0
    0%
    Disease Severity: Critical Day 8 Ordinal Scale = 6
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: Critical Day 8 Ordinal Scale = 7
    13.6
    15.1%
    7.4
    4%
    15.9
    8.8%
    Disease Severity: Critical Day 11 Ordinal Scale = 1
    9.1
    10.1%
    21.3
    11.4%
    11.4
    6.3%
    Disease Severity: Critical Day 11 Ordinal Scale = 2
    45.5
    50.6%
    41.5
    22.2%
    37.5
    20.8%
    Disease Severity: Critical Day 11 Ordinal Scale = 3
    0
    0%
    6.4
    3.4%
    2.3
    1.3%
    Disease Severity: Critical Day 11 Ordinal Scale = 4
    20.5
    22.8%
    11.7
    6.3%
    19.3
    10.7%
    Disease Severity: Critical Day 11 Ordinal Scale = 5
    0
    0%
    2.1
    1.1%
    2.3
    1.3%
    Disease Severity: Critical Day 11 Ordinal Scale = 6
    0
    0%
    0
    0%
    1.1
    0.6%
    Disease Severity: Critical Day 11 Ordinal Scale = 7
    25.0
    27.8%
    17.0
    9.1%
    26.1
    14.5%
    Disease Severity: Critical Day 15 Ordinal Scale = 1
    18.2
    20.2%
    27.7
    14.8%
    13.6
    7.6%
    Disease Severity: Critical Day 15 Ordinal Scale = 2
    36.4
    40.4%
    24.5
    13.1%
    29.5
    16.4%
    Disease Severity: Critical Day 15 Ordinal Scale = 3
    0
    0%
    3.2
    1.7%
    1.1
    0.6%
    Disease Severity: Critical Day 15 Ordinal Scale = 4
    13.6
    15.1%
    19.1
    10.2%
    14.8
    8.2%
    Disease Severity: Critical Day 15 Ordinal Scale = 5
    0
    0%
    3.2
    1.7%
    1.1
    0.6%
    Disease Severity: Critical Day 15 Ordinal Scale = 6
    0
    0%
    1.1
    0.6%
    1.1
    0.6%
    Disease Severity: Critical Day 15 Ordinal Scale = 7
    31.8
    35.3%
    21.3
    11.4%
    38.6
    21.4%
    Disease Severity: Critical Day 29 Ordinal Scale = 1
    27.3
    30.3%
    37.2
    19.9%
    25.0
    13.9%
    Disease Severity: Critical Day 29 Ordinal Scale = 2
    27.3
    30.3%
    7.4
    4%
    5.7
    3.2%
    Disease Severity: Critical Day 29 Ordinal Scale = 3
    0
    0%
    2.1
    1.1%
    0
    0%
    Disease Severity: Critical Day 29 Ordinal Scale = 4
    4.5
    5%
    4.3
    2.3%
    9.1
    5.1%
    Disease Severity: Critical Day 29 Ordinal Scale = 5
    0
    0%
    2.1
    1.1%
    3.4
    1.9%
    Disease Severity: Critical Day 29 Ordinal Scale = 6
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: Critical Day 29 Ordinal Scale = 7
    40.9
    45.4%
    46.8
    25%
    56.8
    31.6%
    Disease Severity: MSOD Day 1 Ordinal Scale = 1
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: MSOD Day 1 Ordinal Scale = 2
    100
    111.1%
    100
    53.5%
    100
    55.6%
    Disease Severity: MSOD Day 1 Ordinal Scale = 3
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: MSOD Day 1 Ordinal Scale = 4
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: MSOD Day 1 Ordinal Scale = 5
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: MSOD Day 1 Ordinal Scale = 6
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: MSOD Day 1 Ordinal Scale = 7
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: MSOD Day 3 Ordinal Scale = 1
    0
    0%
    4.7
    2.5%
    2.4
    1.3%
    Disease Severity: MSOD Day 3 Ordinal Scale = 2
    100
    111.1%
    95.3
    51%
    97.6
    54.2%
    Disease Severity: MSOD Day 3 Ordinal Scale = 3
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: MSOD Day 3 Ordinal Scale = 4
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: MSOD Day 3 Ordinal Scale = 5
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: MSOD Day 3 Ordinal Scale = 6
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: MSOD Day 3 Ordinal Scale = 7
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: MSOD Day 5 Ordinal Scale = 1
    9.5
    10.6%
    9.3
    5%
    14.6
    8.1%
    Disease Severity: MSOD Day 5 Ordinal Scale = 2
    90.5
    100.6%
    88.4
    47.3%
    82.9
    46.1%
    Disease Severity: MSOD Day 5 Ordinal Scale = 3
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: MSOD Day 5 Ordinal Scale = 4
    0
    0%
    2.3
    1.2%
    2.4
    1.3%
    Disease Severity: MSOD Day 5 Ordinal Scale = 5
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: MSOD Day 5 Ordinal Scale = 6
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: MSOD Day 5 Ordinal Scale = 7
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: MSOD Day 8 Ordinal Scale = 1
    19.0
    21.1%
    14.0
    7.5%
    19.5
    10.8%
    Disease Severity: MSOD Day 8 Ordinal Scale = 2
    71.4
    79.3%
    69.8
    37.3%
    75.6
    42%
    Disease Severity: MSOD Day 8 Ordinal Scale = 3
    9.5
    10.6%
    0
    0%
    0
    0%
    Disease Severity: MSOD Day 8 Ordinal Scale = 4
    0
    0%
    14.0
    7.5%
    4.9
    2.7%
    Disease Severity: MSOD Day 8 Ordinal Scale = 5
    0
    0%
    2.3
    1.2%
    0
    0%
    Disease Severity: MSOD Day 8 Ordinal Scale = 6
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: MSOD Day 8 Ordinal Scale = 7
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: MSOD Day 11 Ordinal Scale = 1
    19.0
    21.1%
    25.6
    13.7%
    26.8
    14.9%
    Disease Severity: MSOD Day 11 Ordinal Scale = 2
    66.7
    74.1%
    46.5
    24.9%
    61.0
    33.9%
    Disease Severity: MSOD Day 11 Ordinal Scale = 3
    4.8
    5.3%
    4.7
    2.5%
    0
    0%
    Disease Severity: MSOD Day 11 Ordinal Scale = 4
    9.5
    10.6%
    11.6
    6.2%
    7.3
    4.1%
    Disease Severity: MSOD Day 11 Ordinal Scale = 5
    0
    0%
    4.7
    2.5%
    0
    0%
    Disease Severity: MSOD Day 11 Ordinal Scale = 6
    0
    0%
    2.3
    1.2%
    2.4
    1.3%
    Disease Severity: MSOD Day 11 Ordinal Scale = 7
    0
    0%
    4.7
    2.5%
    2.4
    1.3%
    Disease Severity: MSOD Day 15 Ordinal Scale = 1
    23.8
    26.4%
    34.9
    18.7%
    31.7
    17.6%
    Disease Severity: MSOD Day 15 Ordinal Scale = 2
    38.1
    42.3%
    34.9
    18.7%
    51.2
    28.4%
    Disease Severity: MSOD Day 15 Ordinal Scale = 3
    0
    0%
    2.3
    1.2%
    0
    0%
    Disease Severity: MSOD Day 15 Ordinal Scale = 4
    33.3
    37%
    2.3
    1.2%
    9.8
    5.4%
    Disease Severity: MSOD Day 15 Ordinal Scale = 5
    0
    0%
    7.0
    3.7%
    0
    0%
    Disease Severity: MSOD Day 15 Ordinal Scale = 6
    0
    0%
    0
    0%
    0
    0%
    Disease Severity: MSOD Day 15 Ordinal Scale = 7
    4.8
    5.3%
    18.6
    9.9%
    7.3
    4.1%
    Disease Severity: MSOD Day 29 Ordinal Scale = 1
    33.3
    37%
    41.9
    22.4%
    39.0
    21.7%
    Disease Severity: MSOD Day 29 Ordinal Scale = 2
    19.0
    21.1%
    14.0
    7.5%
    14.6
    8.1%
    Disease Severity: MSOD Day 29 Ordinal Scale = 3
    0
    0%
    2.3
    1.2%
    4.9
    2.7%
    Disease Severity: MSOD Day 29 Ordinal Scale = 4
    9.5
    10.6%
    2.3
    1.2%
    9.8
    5.4%
    Disease Severity: MSOD Day 29 Ordinal Scale = 5
    0
    0%
    7.0
    3.7%
    9.8
    5.4%
    Disease Severity: MSOD Day 29 Ordinal Scale = 6
    0
    0%
    4.7
    2.5%
    0
    0%
    Disease Severity: MSOD Day 29 Ordinal Scale = 7
    33.3
    37%
    27.9
    14.9%
    22.0
    12.2%
    Disease Severity: MSOD Day 29 Ordinal Scale = Missing
    0
    0%
    0
    0%
    1.1
    0.6%
    13. Secondary Outcome
    Title Time to Discharge or to a National Early Warning Score 2 (NEWS2) of ≤2 and Maintained for 24 Hours (Phase 2)
    Description NEWS2 was used to standardize assessment of acute-illness severity, track clinical condition of participants and to alert clinical teams to participant deterioration. NEWS2 score was based on 7 clinical parameters: respiration rate, oxygen saturation, supplemental oxygen, systolic blood pressure, pulse rate, level of consciousness, and temperature. A score of 0, 1, 2, and 3 was allocated to each parameter except supplemental oxygen (a score of 0 or 1 was allocated) and level of consciousness (a score of 0 or 3 was allocated), where 0 = normal health condition to 3 = worst health condition; higher score indicated more severity. All scores were summed to get an aggregate score. Aggregate NEWS2 score ranged from 0 to 19, with higher scores meaning more severity/higher risk: low risk (score 0 to 4); low to medium risk (score of 3 in any individual parameter); medium risk (score 5 to 6); high risk (score 7 to 19).
    Time Frame Up to day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 ITT population
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 90 187 180
    Disease Severity: Severe
    6.0
    6.0
    6.0
    Disease Severity: Critical
    NA
    25.0
    15.0
    Disease Severity: MSOD
    NA
    NA
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: Severe
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6987
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.97
    Confidence Interval (2-Sided) 95%
    0.59 to 1.59
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: Severe
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0453
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.65
    Confidence Interval (2-Sided) 95%
    0.39 to 1.09
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: Critical
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9734
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.23
    Confidence Interval (2-Sided) 95%
    0.73 to 2.09
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: Critical
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0040
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No)
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.91
    Confidence Interval (2-Sided) 95%
    1.14 to 3.20
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: MSOD
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9551
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.97
    Confidence Interval (2-Sided) 95%
    0.43 to 2.17
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: MSOD
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8722
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.94
    Confidence Interval (2-Sided) 95%
    0.42 to 2.10
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    14. Secondary Outcome
    Title Change From Baseline in NEWS2 Scoring System (Phase 2)
    Description NEWS2 was used to standardize assessment of acute-illness severity, track clinical condition of participants and to alert clinical teams to participant deterioration. NEWS2 score was based on 7 clinical parameters: respiration rate, oxygen saturation, supplemental oxygen, systolic blood pressure, pulse rate, level of consciousness, and temperature. A score of 0, 1, 2, and 3 was allocated to each parameter except supplemental oxygen (a score of 0 or 1 was allocated) and level of consciousness (a score of 0 or 3 was allocated), where 0 = normal health condition to 3 = worst health condition; higher score indicated more severity. All scores were summed to get an aggregate score. Aggregate NEWS2 score ranged from 0 to 19, with higher scores meaning more severity/higher risk: low risk (score 0 to 4); low to medium risk (score of 3 in any individual parameter); medium risk (score 5 to 6); high risk (score 7 to 19).
    Time Frame Days 3, 5, 8, 11, 15 and 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 ITT population with NEWS2 score reported at baseline
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 72 151 147
    Day 3
    0.46
    (2.29)
    0.14
    (2.69)
    0.03
    (3.00)
    Day 5
    0.36
    (3.18)
    0.00
    (2.98)
    0.03
    (3.26)
    Day 8
    -0.17
    (3.05)
    -0.22
    (3.33)
    -0.31
    (3.65)
    Day 11
    0.00
    (3.53)
    -0.27
    (3.65)
    -0.29
    (4.29)
    Day 15
    -0.40
    (3.55)
    -0.45
    (3.91)
    -0.48
    (4.50)
    Day 29
    -0.67
    (4.12)
    -1.12
    (4.23)
    -1.34
    (4.75)
    15. Secondary Outcome
    Title Number of Days With Fever (Phase 2)
    Description Defined as ≥38°C (oral), ≥38.4°C (rectal or tympanic) or ≥37.6°C (temporal or axillary)
    Time Frame Up to Day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 ITT population
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 90 187 180
    Mean (Standard Deviation) [Days]
    6.3
    (5.92)
    4.2
    (4.37)
    5.8
    (7.49)
    16. Secondary Outcome
    Title Percentage of Participants Alive, Off Oxygen (Phase 2)
    Description
    Time Frame At Day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 ITT population
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 90 187 180
    Disease Severity: Severe
    92.0
    102.2%
    92.0
    49.2%
    70.6
    39.2%
    Disease Severity: Critical
    40.9
    45.4%
    50.0
    26.7%
    61.4
    34.1%
    Disease Severity: MSOD
    38.1
    42.3%
    39.5
    21.1%
    34.1
    18.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: Severe
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 1.0000
    Comments
    Method Chi-squared
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: Severe
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0353
    Comments
    Method Chi-squared
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: Critical
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3187
    Comments
    Method Chi-squared
    Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: Critical
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0261
    Comments
    Method Chi-squared
    Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: MSOD
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9117
    Comments
    Method Chi-squared
    Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: MSOD
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7584
    Comments
    Method Chi-squared
    Comments
    17. Secondary Outcome
    Title Number of Days of Resting Respiratory Rate >24 Breaths/Min (Phase 2)
    Description
    Time Frame Up to day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 ITT population
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 90 187 180
    Mean (Standard Deviation) [Days]
    9.2
    (10.29)
    7.3
    (8.21)
    8.2
    (7.99)
    18. Secondary Outcome
    Title Number of Days With Hypoxemia (Phase 2)
    Description
    Time Frame Up to day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 ITT population
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 90 187 180
    Mean (Standard Deviation) [Days]
    18.1
    (14.16)
    14.5
    (11.96)
    16.4
    (13.94)
    19. Secondary Outcome
    Title Number of Days of Supplemental Oxygen Use (Phase 2)
    Description
    Time Frame Up to day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 ITT population
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 90 187 180
    Mean (Standard Deviation) [days]
    17.7
    (14.15)
    14.1
    (11.92)
    16.2
    (14.02)
    20. Secondary Outcome
    Title Time to Saturation ≥94% on Room Air (Phase 2)
    Description
    Time Frame Up to day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 ITT population
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 90 187 180
    Disease Severity: Severe
    NA
    NA
    NA
    Disease Severity: Critical
    NA
    NA
    NA
    Disease Severity: MSOD
    5.0
    NA
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: Severe
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0385
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.32
    Confidence Interval (2-Sided) 95%
    0.11 to 0.94
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: Severe
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0782
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.38
    Confidence Interval (2-Sided) 95%
    0.14 to 1.05
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: Critical
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2436
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.22
    Confidence Interval (2-Sided) 95%
    0.70 to 2.14
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: Critical
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3223
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.83
    Confidence Interval (2-Sided) 95%
    0.46 to 1.51
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Disease Severity: MSOD
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4670
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.74
    Confidence Interval (2-Sided) 95%
    0.36 to 1.52
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Disease Severity: MSOD
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3728
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.71
    Confidence Interval (2-Sided) 95%
    0.35 to 1.47
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    21. Secondary Outcome
    Title Number of Ventilator Free Days (Phase 2)
    Description Summary of Ventilator-free days during study in Participants using Invasive Mechanical Ventilation at Baseline
    Time Frame Up to Day 22

    Outcome Measure Data

    Analysis Population Description
    Phase 2 ITT population
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 90 187 180
    Disease Severity: Severe
    19.9
    (4.2)
    19.7
    (4.7)
    15.5
    (9.1)
    Disease Severity: Critical
    8.9
    (9.6)
    7.6
    (8.5)
    10.9
    (9.3)
    Disease Severity: MSOD
    4.5
    (5.5)
    4.6
    (6.5)
    3.3
    (5.1)
    22. Secondary Outcome
    Title Number of Participants Who Initiated Mechanical Ventilation After Baseline (Phase 2)
    Description
    Time Frame Up to Day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 ITT population not on Invasive mechanical ventilation or ECMO at baseline
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 90 187 180
    Disease Severity: Severe
    2
    2.2%
    4
    2.1%
    9
    5%
    Disease Severity: Critical
    13
    14.4%
    14
    7.5%
    11
    6.1%
    Disease Severity: MSOD
    0
    0%
    0
    0%
    0
    0%
    23. Secondary Outcome
    Title Number of Days in an Intensive Care Unit (ICU) in Participants Who Were Not in ICU at Baseline (Phase 2)
    Description
    Time Frame Up to Day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 ITT population participants who were not in ICU at baseline
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 39 70 67
    Mean (Standard Deviation) [Days]
    13.6
    (11.0)
    11.4
    (10.5)
    13.8
    (15.5)
    24. Secondary Outcome
    Title Number of Days of Hospitalization Among Survivors (Phase 2)
    Description
    Time Frame Up to day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 ITT population participants with a hospital discharge date on or before Day 29
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 66 127 131
    Up to Day 8
    7.3
    (1.3)
    7.3
    (1.3)
    7.2
    (1.5)
    Up to Day 15
    13.7
    (2.0)
    13.5
    (2.2)
    13.5
    (2.2)
    Up to Day 22
    21.3
    (1.8)
    21.2
    (1.7)
    21.6
    (1.1)
    Up to Day 29
    27.3
    (2.5)
    27.5
    (2.2)
    28.4
    (1.4)
    25. Secondary Outcome
    Title Number of Deaths Due to Any Cause
    Description Number of deaths due to any cause (All-Cause Mortality)
    Time Frame Up to day 60

    Outcome Measure Data

    Analysis Population Description
    ITT population
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: 200mg IV - Critical Phase 3 Cohort 1:Sarilumab 400mg IV - Critical Phase 3 Cohort 1: Placebo - Severe Phase 3 Cohort 1: Sarilumab 200mg IV - Severe Phase 3 Cohort 1: Sarilumab 400mg IV - Severe Phase 3 Cohort 1: Placebo - MSOD Phase 3 Cohort 1: Sarilumab 200mg IV - MSOD Phase 3 Cohort 1: Sarilumab 400mg IV - MSOD Phase 3 Cohort 1: Placebo - Immunocompromised Phase 3 Cohort 1: Sarilumab 200mg IV - Immunocompromised Phase 3 Cohort 1: Sarilumab 400mg IV - Immunocompromised Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800 mg IV Phase 3 Cohort 3: Placebo Phase 3 Cohort 3: Sarilumab 800 mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD)[vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline
    Measure Participants 90 187 180 170 242 338 70 140 137 46 95 92 8 12 15 15 16 6 2
    Number [deaths]
    24
    60
    49
    59
    70
    114
    9
    12
    21
    16
    40
    40
    3
    4
    6
    4
    3
    1
    0
    26. Secondary Outcome
    Title Percentage of Participants With at Least 1-point Improvement in Clinical Status Using the 7-point Ordinal Scale in Participants With Critical COVID-19 (Phase 3 Cohort 1: Critical ITT)
    Description The ordinal scale is an assessment of the clinical status of a participant. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity
    Time Frame Day 22

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1 Critical ITT population
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 170 242 338
    Number (95% Confidence Interval) [Percentage of Participants]
    54.1
    60.1%
    56.6
    30.3%
    51.5
    28.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5851
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 2.7
    Confidence Interval (2-Sided) 95%
    -7.0 to 12.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5767
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -2.6
    Confidence Interval (2-Sided) 95%
    -11.7 to 6.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    27. Secondary Outcome
    Title Percentage of Participants Who Recover (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)
    Description Percentage of Participants Who Recover (Discharged, or Alive without Supplemental Oxygen Use or at Pre-COVID Oxygen Use) at Day 22
    Time Frame Day 22

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1 Critical population receiving mechanical ventilation at baseline
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 62 104 132
    Number (95% Confidence Interval) [Percentage of Participants]
    25.8
    28.7%
    30.8
    16.5%
    31.8
    17.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4777
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 5.2
    Confidence Interval (2-Sided) 95%
    -9.4 to 18.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4202
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 5.7
    Confidence Interval (2-Sided) 95%
    -8.4 to 18.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    28. Secondary Outcome
    Title Percentage of Participants Who Recover (Phase 3 Cohort 1: Critical ITT)
    Description Percentage of Participants Who Recover (Discharged, or Alive without Supplemental Oxygen Use or at Pre-COVID Oxygen Use) at Day 22
    Time Frame Day 22

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1 Critical ITT
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 170 242 338
    Number (95% Confidence Interval) [Percentage of Participants]
    50.0
    55.6%
    49.6
    26.5%
    45.3
    25.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9696
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 0.2
    Confidence Interval (2-Sided) 95%
    -9.5 to 9.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3152
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -4.7
    Confidence Interval (2-Sided) 95%
    -13.8 to 4.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    29. Secondary Outcome
    Title Percentage of Participants Who Die (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)
    Description Percentage of Participants who die through Day 29 and Day 60
    Time Frame Up to Day 29 and Day 60

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1 Critical population receiving mechanical ventilation at baseline
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 62 104 132
    Through Day 29
    41.9
    46.6%
    33.7
    18%
    36.4
    20.2%
    Through Day 60
    51.6
    57.3%
    37.5
    20.1%
    39.4
    21.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Through Day 29
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3217
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -7.7
    Confidence Interval (2-Sided) 95%
    -22.8 to 7.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Through Day 29
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4630
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -5.5
    Confidence Interval (2-Sided) 95%
    -20.2 to 8.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Through Day 60
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0971
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -13.3
    Confidence Interval (2-Sided) 95%
    -28.2 to 2.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Through Day 60
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1193
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -11.9
    Confidence Interval (2-Sided) 95%
    -26.4 to 2.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    30. Secondary Outcome
    Title Percentage of Participants Who Die (Phase 3 Cohort 1: Critical ITT)
    Description Percentage of Participants who die through Day 29 and Day 60
    Time Frame Up to Day 29 and Day 60

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1 Critical ITT population
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 170 242 338
    Through Day 29
    25.3
    28.1%
    24.8
    13.3%
    30.5
    16.9%
    Through Day 60
    34.7
    38.6%
    28.9
    15.5%
    33.7
    18.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Through Day 29
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8844
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -0.6
    Confidence Interval (2-Sided) 95%
    -9.3 to 7.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Through Day 29
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2247
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 5.2
    Confidence Interval (2-Sided) 95%
    -3.3 to 13.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Through Day 60
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2102
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -13.3
    Confidence Interval (2-Sided) 95%
    -28.2 to 2.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Through Day 60
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8292
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -11.9
    Confidence Interval (2-Sided) 95%
    -26.4 to 2.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    31. Secondary Outcome
    Title Percentage of Participants Alive Not Receiving Mechanical Ventilation or ECMO at Day 22 (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)
    Description Percentage of participants alive not receiving mechanical ventilation or ECMO at Day 22 (Phase 3 Cohort 1)
    Time Frame At Day 22

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1 - Critical population receiving mechanical ventilation at baseline
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 62 104 132
    Number (95% Confidence Interval) [Percentage of Participants]
    35.5
    39.4%
    46.2
    24.7%
    44.7
    24.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2203
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 9.8
    Confidence Interval (2-Sided) 95%
    -6.0 to 24.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2483
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 8.8
    Confidence Interval (2-Sided) 95%
    -6.1 to 22.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    32. Secondary Outcome
    Title Percentage of Participants With at Least a 2-point Improvement in Clinical Status From Baseline to Day 22 Using the 7-point Ordinal Scale (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)
    Description Percentage of participants with at least a 2-point improvement in clinical status from baseline to Day 22 using the 7-point ordinal scale. The ordinal scale is an assessment of the clinical status of a participant. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity
    Time Frame At Day 22

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1: Critical population receiving mechanical ventilation at baseline
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 62 104 132
    Number (95% Confidence Interval) [Percentage of Participants]
    33.9
    37.7%
    38.5
    20.6%
    40.2
    22.3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6020
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 4.1
    Confidence Interval (2-Sided) 95%
    -11.2 to 18.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4342
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 5.9
    Confidence Interval (2-Sided) 95%
    -8.9 to 19.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    33. Secondary Outcome
    Title Percentage of Participants Alive Not Receiving Mechanical Ventilation or ECMO at Day 22 (Phase 3 Cohort 1: Critical ITT)
    Description Percentage of participants alive not receiving mechanical ventilation or ECMO at Day 22 (Phase 3 Cohort 1)
    Time Frame At Day 22

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1: Critical ITT population
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 170 242 338
    Number (95% Confidence Interval) [Percentage of Participants]
    58.8
    65.3%
    63.6
    34%
    55.9
    31.1%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2896
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 5.2
    Confidence Interval (2-Sided) 95%
    -4.3 to 14.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5355
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -2.9
    Confidence Interval (2-Sided) 95%
    -11.8 to 6.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    34. Secondary Outcome
    Title Percentage of Participants With at Least a 2-point Improvement in Clinical Status From Baseline to Day 22 Using the 7-point Ordinal Scale (Phase 3 Cohort 1: Critical ITT)
    Description Percentage of participants with at least a 2-point improvement in clinical status from baseline to Day 22 using the 7-point ordinal scale. The ordinal scale is an assessment of the clinical status of a participant. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity
    Time Frame At Day 22

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1: Critical ITT population
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 170 242 338
    Number (95% Confidence Interval) [Percentage of Participants]
    52.4
    58.2%
    52.5
    28.1%
    47.6
    26.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9210
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 0.5
    Confidence Interval (2-Sided) 95%
    -9.2 to 10.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3174
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -4.7
    Confidence Interval (2-Sided) 95%
    -13.8 to 4.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    35. Secondary Outcome
    Title Time to at Least 1-point Improvement in Clinical Status Assessment on the 7-point Ordinal Scale (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)
    Description The ordinal scale is an assessment of the clinical status of a participant. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity
    Time Frame Up to day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1 Critical populations receiving mechanical ventilation at baseline
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 62 104 132
    Median (95% Confidence Interval) [Days]
    NA
    27.0
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0705
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.62
    Confidence Interval (2-Sided) 95%
    0.98 to 2.66
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1800
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.50
    Confidence Interval (2-Sided) 95%
    0.92 to 2.43
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    36. Secondary Outcome
    Title Time to at Least 1-point Improvement in Clinical Status Assessment on the 7-point Ordinal Scale (Phase 3 Cohort 1: Critical ITT)
    Description The ordinal scale is an assessment of the clinical status of a participant. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity
    Time Frame Up to day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1 Critical ITT population
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 170 242 338
    Median (95% Confidence Interval) [Days]
    19.5
    16.0
    18.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1831
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.18
    Confidence Interval (2-Sided) 95%
    0.91 to 1.52
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8770
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.05
    Confidence Interval (2-Sided) 95%
    0.82 to 1.34
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    37. Secondary Outcome
    Title Time to at Least 1-point Improvement in Clinical Status Assessment on the 7-point Ordinal Scale (Phase 3 Cohort 2)
    Description The ordinal scale is an assessment of the clinical status of a participant. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity
    Time Frame Up to day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 2 Critical population receiving mechanical ventilation at baseline
    Arm/Group Title Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19
    Measure Participants 15 16
    Median (95% Confidence Interval) [Days]
    17.0
    15.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7103
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.85
    Confidence Interval (2-Sided) 95%
    0.35 to 2.06
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    38. Secondary Outcome
    Title Time to at Least 2-point Improvement in Clinical Status Assessment on the 7-point Ordinal Scale (Phase 3 Cohort 1)
    Description The ordinal scale is an assessment of the clinical status of a participant. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity
    Time Frame Up to day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1: Critical population receiving mechanical ventilation at baseline
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 62 104 132
    Median (95% Confidence Interval) [days]
    NA
    NA
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1512
    Comments P-value from stratified log-rank test
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.47
    Confidence Interval (2-Sided) 95%
    0.89 to 2.43
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2952
    Comments P-value from stratified log-rank test
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.38
    Confidence Interval (2-Sided) 95%
    0.85 to 2.24
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    39. Secondary Outcome
    Title Time to at Least 2-point Improvement in Clinical Status Assessment on the 7-point Ordinal Scale (Phase 3 Cohort 1: Critical ITT)
    Description The ordinal scale is an assessment of the clinical status of a participant. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized; higher score = less severity
    Time Frame Up to day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1: Critical ITT population
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 170 242 338
    Median (95% Confidence Interval) [days]
    22.0
    19.0
    23.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2297
    Comments P-value from stratified log-rank test
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.16
    Confidence Interval (2-Sided) 95%
    0.89 to 1.50
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8651
    Comments P-value from stratified log-rank test
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.01
    Confidence Interval (2-Sided) 95%
    0.79 to 1.30
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    40. Secondary Outcome
    Title Percentage of Participants Receiving Mechanical Ventilation or ECMO at Day 22 (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)
    Description
    Time Frame Day 22

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1: Critical population receiving mechanical ventilation at baseline
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 62 104 132
    Number (95% Confidence Interval) [Percentage of Participants]
    25.8
    28.7%
    24.0
    12.8%
    23.5
    13.1%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8864
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -1.0
    Confidence Interval (2-Sided) 95%
    -15.2 to 12.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7500
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -2.1
    Confidence Interval (2-Sided) 95%
    -15.8 to 10.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    41. Secondary Outcome
    Title Percentage of Participants Receiving Mechanical Ventilation or ECMO at Day 22 (Phase 3 Cohort 1: Critical ITT)
    Description
    Time Frame Day 22

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1: Critical ITT population
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 170 242 338
    Number (95% Confidence Interval) [Percentage of Participants]
    17.1
    19%
    15.7
    8.4%
    17.5
    9.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6858
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -1.5
    Confidence Interval (2-Sided) 95%
    -9.1 to 5.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9173
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 0.4
    Confidence Interval (2-Sided) 95%
    -7.0 to 7.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    42. Secondary Outcome
    Title Percentage of Patients Discharged and Alive (Phase 3 Cohort 1)
    Description Percentage of Patients Discharged and Alive at Day 22
    Time Frame At Day 22

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1: Critical population receiving mechanical ventilation at baseline
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 62 104 132
    Number (95% Confidence Interval) [Percentage of Participants]
    22.6
    25.1%
    26.9
    14.4%
    26.5
    14.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5239
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 4.5
    Confidence Interval (2-Sided) 95%
    -9.7 to 17.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5809
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 3.7
    Confidence Interval (2-Sided) 95%
    -10.0 to 15.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    43. Secondary Outcome
    Title Percentage of Participants Discharged and Alive at Day 22 (Phase 3 Cohort 1: Critical ITT)
    Description Percentage of Participants Discharged and Alive at Day 22
    Time Frame At Day 22

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1: Critical ITT population
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 170 242 338
    Number (95% Confidence Interval) [Percentage of Participants]
    47.6
    52.9%
    47.5
    25.4%
    42.6
    23.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9343
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 0.4
    Confidence Interval (2-Sided) 95%
    -9.3 to 10.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2822
    Comments P-value based on stratified Cochran-Mantel-Haenszel test using the strata Use of Steroids at Baseline.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -5.0
    Confidence Interval (2-Sided) 95%
    -14.1 to 4.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    44. Secondary Outcome
    Title Time to Recovery (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)
    Description Phase 3 Cohort 1 Time to Recovery (Discharged, or Alive without Supplemental Oxygen Use or at Pre-COVID Oxygen Use)
    Time Frame Up to day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1 Critical population receiving mechanical ventilation at baseline
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 62 104 132
    Median (95% Confidence Interval) [days]
    NA
    NA
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4519
    Comments P-value from stratified log-rank test
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.28
    Confidence Interval (2-Sided) 95%
    0.75 to 2.18
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2818
    Comments P-value from stratified log-rank test
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.35
    Confidence Interval (2-Sided) 95%
    0.81 to 2.24
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    45. Secondary Outcome
    Title Time to Recovery (Phase 3 Cohort 1: Critical ITT)
    Description Phase 3 Cohort 1 Time to Recovery (Discharged, or Alive without Supplemental Oxygen Use or at Pre-COVID Oxygen Use)
    Time Frame Up to day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1: Critical ITT population
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 170 242 338
    Median (95% Confidence Interval) [days]
    25.5
    23.0
    27.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4674
    Comments P-value from stratified log-rank test
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.09
    Confidence Interval (2-Sided) 95%
    0.84 to 1.43
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8503
    Comments P-value from stratified log-rank test.
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.00
    Confidence Interval (2-Sided) 95%
    0.77 to 1.28
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    46. Secondary Outcome
    Title Time to Recovery (Phase 3 Cohort 2)
    Description Time to Recovery (Discharged, or Alive without Supplemental Oxygen Use or at Pre-COVID Oxygen Use)
    Time Frame Up to day 29

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 2 population receiving mechanical ventilation at baseline
    Arm/Group Title Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19
    Measure Participants 15 16
    Median (95% Confidence Interval) [days]
    23.0
    22.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6156
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.79
    Confidence Interval (2-Sided) 95%
    0.31 to 2.02
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    47. Secondary Outcome
    Title Time to Death (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)
    Description Phase 3 Cohort 1 Time to Death (All-Cause Mortality)
    Time Frame Up to day 60

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1 Critical population receiving mechanical ventilation at baseline
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 62 104 132
    Median (95% Confidence Interval) [days]
    41.0
    NA
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0843
    Comments P-value from stratified log-rank test
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.65
    Confidence Interval (2-Sided) 95%
    0.41 to 1.03
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1576
    Comments P-value from stratified log-rank test
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.69
    Confidence Interval (2-Sided) 95%
    0.44 to 1.07
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    48. Secondary Outcome
    Title Time to Death (Phase 3 Cohort 1: Critical ITT)
    Description Time to Death (All-Cause Mortality)
    Time Frame Up to day 60

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1: Critical ITT population
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 170 242 338
    Median (95% Confidence Interval) [days]
    NA
    NA
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1980
    Comments P-value from stratified log-rank test
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.81
    Confidence Interval (2-Sided) 95%
    0.57 to 1.14
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7973
    Comments P-value from stratified log-rank test.
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.00
    Confidence Interval (2-Sided) 95%
    0.73 to 1.36
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    49. Secondary Outcome
    Title Time to Death (Phase 3 Cohort 2)
    Description Time to Death (All-Cause Mortality)
    Time Frame Up to day 60

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 2 population receiving mechanical ventilation at baseline
    Arm/Group Title Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19
    Measure Participants 15 16
    Median (95% Confidence Interval) [days]
    NA
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5023
    Comments P-value based on log-rank test stratified by use of systemic corticosteroids for COVID-19 (Yes, No).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.60
    Confidence Interval (2-Sided) 95%
    0.13 to 2.75
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    50. Secondary Outcome
    Title Number of Ventilator-Free Days (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)
    Description Number of Ventilator-Free days up to Day 29 (Phase 3 Cohort 1)
    Time Frame Days 8, 15, 22 and 29

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1: Critical population receiving mechanical ventilation at baseline
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 62 104 132
    Ventilator-free days up to Day 8
    0.6
    (1.4)
    0.8
    (1.7)
    0.4
    (1.2)
    Ventilator-free days up to Day 15
    2.2
    (4.0)
    2.8
    (4.4)
    2.2
    (3.7)
    Ventilator-free days up to Day 22
    4.3
    (6.8)
    5.5
    (7.3)
    4.8
    (6.6)
    Ventilator-free days up to Day 29
    6.9
    (9.9)
    8.7
    (10.4)
    8.0
    (9.6)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Ventilator-free days up to Day 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2804
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 0.3
    Confidence Interval (2-Sided) 95%
    -0.2 to 0.8
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.26
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Ventilator-free days up to Day 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5023
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -0.1
    Confidence Interval (2-Sided) 95%
    -0.5 to 0.3
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.20
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Ventilator-free days up to Day 15
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3821
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 0.6
    Confidence Interval (2-Sided) 95%
    -0.7 to 1.9
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.68
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Ventilator-free days up to Day 15
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9737
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 0.0
    Confidence Interval (2-Sided) 95%
    -1.2 to 1.1
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.59
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Ventilator-free days up to Day 22
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3179
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 1.2
    Confidence Interval (2-Sided) 95%
    -1.1 to 3.4
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.15
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Ventilator-free days up to Day 22
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6302
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 0.5
    Confidence Interval (2-Sided) 95%
    -1.5 to 2.5
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.03
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Ventilator-free days up to Day 29
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2862
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 1.8
    Confidence Interval (2-Sided) 95%
    -1.5 to 5.0
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.64
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Ventilator-free days up to Day 29
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4509
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 1.1
    Confidence Interval (2-Sided) 95%
    -1.8 to 4.1
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.49
    Estimation Comments
    51. Secondary Outcome
    Title Number of Ventilator-Free Days (Phase 3 Cohort 1: Critical ITT)
    Description Number of Ventilator-Free days up to Day 29 (Phase 3 Cohort 1)
    Time Frame Days 8, 15, 22 and 29

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1: Critical ITT population
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 170 242 338
    Ventilator-free days up to Day 8
    3.6
    (3.3)
    3.5
    (3.3)
    3.2
    (3.3)
    Ventilator-free days up to Day 15
    7.2
    (6.5)
    7.2
    (6.4)
    6.4
    (6.4)
    Ventilator-free days up to Day 22
    11.1
    (9.7)
    11.3
    (9.4)
    9.9
    (9.4)
    Ventilator-free days up to Day 29
    15.3
    (12.8)
    15.5
    (12.4)
    13.9
    (12.5)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Ventilator-free days up to Day 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5640
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -0.2
    Confidence Interval (2-Sided) 95%
    -0.8 to 0.5
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.33
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Ventilator-free days up to Day 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1602
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -0.4
    Confidence Interval (2-Sided) 95%
    -1.0 to 0.2
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.31
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Ventilator-free days up to Day 15
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9144
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -0.1
    Confidence Interval (2-Sided) 95%
    -1.3 to 1.2
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.64
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Ventilator-free days up to Day 15
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1450
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -0.9
    Confidence Interval (2-Sided) 95%
    -2.1 to 0.3
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.61
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Ventilator-free days up to Day 22
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8378
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 0.2
    Confidence Interval (2-Sided) 95%
    -1.7 to 2.1
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.95
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Ventilator-free days up to Day 22
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1988
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -1.2
    Confidence Interval (2-Sided) 95%
    -2.9 to 0.6
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.89
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Ventilator-free days up to Day 29
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8556
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 0.2
    Confidence Interval (2-Sided) 95%
    -2.2 to 2.7
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.26
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Ventilator-free days up to Day 29
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2630
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -1.3
    Confidence Interval (2-Sided) 95%
    -3.7 to 1.0
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.19
    Estimation Comments
    52. Secondary Outcome
    Title Number of Days of Hospitalization Among Survivors (Phase 3 Cohort 1)
    Description Number of days of hospitalization among survivors (Phase 3 Cohort 1)
    Time Frame Days 8, 15, 22 and 29

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1: Critical population receiving mechanical ventilation at baseline
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 62 104 132
    Hospitalized up to Day 8
    7.7
    (0.9)
    7.8
    (0.6)
    8.0
    (0.2)
    Hospitalized up to Day 15
    14.5
    (1.5)
    14.4
    (1.5)
    14.5
    (1.3)
    Hospitalized up to Day 22
    20.7
    (2.3)
    21.6
    (1.3)
    21.1
    (1.7)
    Hospitalized up to Day 29
    28.3
    (1.8)
    28.5
    (1.4)
    28.2
    (1.6)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Hospitalized up to Day 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3662
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value 0.2
    Confidence Interval (2-Sided) 95%
    -0.2 to 0.5
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.18
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Hospitalized up to Day 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0820
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value 0.3
    Confidence Interval (2-Sided) 95%
    0.0 to 0.6
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.16
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Hospitalized up to Day 15
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6984
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value -0.1
    Confidence Interval (2-Sided) 95%
    -0.9 to 0.6
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.37
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Hospitalized up to Day 15
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9833
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value 0.0
    Confidence Interval (2-Sided) 95%
    -0.6 to 0.6
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.32
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Hospitalized up to Day 22
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1436
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value 0.9
    Confidence Interval (2-Sided) 95%
    -0.3 to 2.0
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.56
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Hospitalized up to Day 22
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4190
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value 0.4
    Confidence Interval (2-Sided) 95%
    -0.6 to 1.4
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.49
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Hospitalized up to Day 29
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6520
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value 0.2
    Confidence Interval (2-Sided) 95%
    -0.7 to 1.2
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.47
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Hospitalized up to Day 29
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8010
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value -0.1
    Confidence Interval (2-Sided) 95%
    -1.1 to 0.9
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.50
    Estimation Comments
    53. Secondary Outcome
    Title Number of Days of Hospitalization Among Survivors (Phase 3 Cohort 1: Critical ITT)
    Description Number of days of hospitalization among survivors (Phase 3 Cohort 1: Critical ITT population)
    Time Frame Days 8, 15, 22 and 29

    Outcome Measure Data

    Analysis Population Description
    Phase 3 Cohort 1: Critical ITT population participants with a hospital discharge date on or before Day 29
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU)
    Measure Participants 111 172 224
    Hospitalized up to Day 8
    7.5
    (1.2)
    7.4
    (1.3)
    7.6
    (1.1)
    Hospitalized up to Day 15
    13.7
    (2.0)
    13.8
    (1.9)
    13.8
    (2.0)
    Hospitalized up to Day 22
    20.8
    (2.0)
    21.1
    (1.8)
    21.2
    (1.7)
    Hospitalized up to Day 29
    28.4
    (1.4)
    28.2
    (1.8)
    28.1
    (1.8)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Hospitalized up to Day 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3724
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value -0.1
    Confidence Interval (2-Sided) 95%
    -0.4 to 0.2
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.16
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Hospitalized up to Day 8
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7034
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value 0.0
    Confidence Interval (2-Sided) 95%
    -0.2 to 0.3
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.13
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Hospitalized up to Day 15
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5841
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value 0.2
    Confidence Interval (2-Sided) 95%
    -0.4 to 0.7
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.28
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Hospitalized up to Day 15
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6648
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value 0.1
    Confidence Interval (2-Sided) 95%
    -0.4 to 0.6
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.27
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Hospitalized up to Day 22
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4624
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value 0.3
    Confidence Interval (2-Sided) 95%
    -0.4 to 1.0
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.36
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Hospitalized up to Day 22
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2546
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value 0.4
    Confidence Interval (2-Sided) 95%
    -0.3 to 1.0
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.32
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 200mg IV
    Comments Hospitalized up to Day 29
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5312
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value -0.2
    Confidence Interval (2-Sided) 95%
    -1.0 to 0.5
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.38
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Phase 2: Placebo, Phase 2: Sarilumab 400mg IV
    Comments Hospitalized up to Day 29
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3039
    Comments p-value using two-sample t-test
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value -0.4
    Confidence Interval (2-Sided) 95%
    -1.1 to 0.3
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.35
    Estimation Comments
    54. Secondary Outcome
    Title Number of Participants With Any Serious Adverse Event
    Description
    Time Frame Up to day 60

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical Phase 3 Cohort 1: Placebo - Severe Phase 3 Cohort 1: Sarilumab 200mg IV - Severe Phase 3 Cohort 1: Sarilumab 400mg IV - Severe Phase 3 Cohort 1: Placebo - MSOD Phase 3 Cohort 1: Sarilumab 200mg IV - MSOD Phase 3 Cohort 1: Sarilumab 400mg IV - MSOD Phase 3 Cohort 1: Placebo - Immunocompromised Phase 3 Cohort 1: Sarilumab 200mg IV - Immunocompromised Phase 3 Cohort 1: Sarilumab 400mg IV - Immunocompromised Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800 mg IV Phase 3 Cohort 3: Placebo Phase 3 Cohort 3: Sarilumab 800 mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline
    Measure Participants 90 187 180 170 242 338 70 140 137 46 95 92 8 12 15 15 16 6 2
    Count of Participants [Participants]
    39
    43.3%
    90
    48.1%
    84
    46.7%
    89
    52.4%
    119
    49.2%
    183
    54.1%
    11
    15.7%
    23
    16.4%
    30
    21.9%
    27
    58.7%
    67
    70.5%
    58
    63%
    3
    37.5%
    6
    50%
    9
    60%
    10
    66.7%
    5
    31.3%
    1
    16.7%
    1
    50%
    55. Secondary Outcome
    Title Number of Participants With Grade 4 Neutropenia (ANC <500/mm3)
    Description Grade 4 Neutropenia defined as Absolute Neutrophil Count (ANC) of less than 500 per cubic millimeter(mm3)
    Time Frame Up to day 60

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical Phase 3 Cohort 1: Placebo - Severe Phase 3 Cohort 1: Sarilumab 200mg IV - Severe Phase 3 Cohort 1: Sarilumab 400mg IV - Severe Phase 3 Cohort 1: Placebo - MSOD Phase 3 Cohort 1: Sarilumab 200mg IV - MSOD Phase 3 Cohort 1: Sarilumab 400mg IV - MSOD Phase 3 Cohort 1: Placebo - Immunocompromised Phase 3 Cohort 1: Sarilumab 200mg IV - Immunocompromised Phase 3 Cohort 1: Sarilumab 400mg IV - Immunocompromised Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800 mg IV Phase 3 Cohort 3: Placebo Phase 3 Cohort 3: Sarilumab 800 mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD)[vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD)[vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD)[vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline
    Measure Participants 90 187 180 170 242 338 70 140 137 46 95 92 8 12 15 15 16 6 2
    Count of Participants [Participants]
    0
    0%
    1
    0.5%
    1
    0.6%
    0
    0%
    2
    0.8%
    1
    0.3%
    0
    0%
    1
    0.7%
    2
    1.5%
    0
    0%
    0
    0%
    2
    2.2%
    0
    0%
    0
    0%
    1
    6.7%
    0
    0%
    1
    6.3%
    0
    0%
    0
    0%
    56. Secondary Outcome
    Title Number of Participants With Severe or Life-threatening Bacterial, Invasive Fungal, or Opportunistic Infection
    Description
    Time Frame Up to day 60

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical Phase 3 Cohort 1: Placebo - Severe Phase 3 Cohort 1: Sarilumab 200mg IV - Severe Phase 3 Cohort 1: Sarilumab 400mg IV - Severe Phase 3 Cohort 1: Placebo - MSOD Phase 3 Cohort 1: Sarilumab 200mg IV - MSOD Phase 3 Cohort 1: Sarilumab 400mg IV - MSOD Phase 3 Cohort 1: Placebo - Immunocompromised Phase 3 Cohort 1: Sarilumab 200mg IV - Immunocompromised Phase 3 Cohort 1: Sarilumab 400mg IV - Immunocompromised Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800 mg IV Phase 3 Cohort 3: Placebo Phase 3 Cohort 3: Sarilumab 800 mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline
    Measure Participants 90 187 180 170 242 338 70 140 137 46 95 92 8 12 15 15 16 6 2
    Count of Participants [Participants]
    14
    15.6%
    17
    9.1%
    25
    13.9%
    36
    21.2%
    53
    21.9%
    72
    21.3%
    2
    2.9%
    2
    1.4%
    10
    7.3%
    16
    34.8%
    30
    31.6%
    28
    30.4%
    1
    12.5%
    4
    33.3%
    3
    20%
    3
    20%
    4
    25%
    1
    16.7%
    1
    50%
    57. Secondary Outcome
    Title Number of Participants With Grade 4 Neutropenia and Concurrent Invasive Infection
    Description
    Time Frame Up to day 60

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical Phase 3 Cohort 1: Placebo - Severe Phase 3 Cohort 1: Sarilumab 200mg IV - Severe Phase 3 Cohort 1: Sarilumab 400mg IV - Severe Phase 3 Cohort 1: Placebo - MSOD Phase 3 Cohort 1: Sarilumab 200mg IV - MSOD Phase 3 Cohort 1: Sarilumab 400mg IV - MSOD Phase 3 Cohort 1: Placebo - Immunocompromised Phase 3 Cohort 1: Sarilumab 200mg IV - Immunocompromised Phase 3 Cohort 1: Sarilumab 400mg IV - Immunocompromised Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800 mg IV Phase 3 Cohort 3: Placebo Phase 3 Cohort 3: Sarilumab 800 mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline
    Measure Participants 90 187 180 170 242 338 70 140 137 46 95 92 8 12 15 15 16 6 2
    Count of Participants [Participants]
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    58. Secondary Outcome
    Title Number of Participants With Grade >=2 Infusion Related Reactions
    Description
    Time Frame Up to day 60

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical Phase 3 Cohort 1: Placebo - Severe Phase 3 Cohort 1: Sarilumab 200mg IV - Severe Phase 3 Cohort 1: Sarilumab 400mg IV - Severe Phase 3 Cohort 1: Placebo - MSOD Phase 3 Cohort 1: Sarilumab 200mg IV - MSOD Phase 3 Cohort 1: Sarilumab 400mg IV - MSOD Phase 3 Cohort 1: Placebo - Immunocompromised Phase 3 Cohort 1: Sarilumab 200mg IV - Immunocompromised Phase 3 Cohort 1: Sarilumab 400mg IV - Immunocompromised Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800 mg IV Phase 3 Cohort 3: Placebo Phase 3 Cohort 3: Sarilumab 800 mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline
    Measure Participants 90 187 180 170 242 338 70 140 137 46 95 92 8 12 15 15 16 6 2
    Count of Participants [Participants]
    0
    0%
    0
    0%
    1
    0.6%
    1
    0.6%
    2
    0.8%
    6
    1.8%
    0
    0%
    0
    0%
    2
    1.5%
    1
    2.2%
    2
    2.1%
    2
    2.2%
    1
    12.5%
    0
    0%
    0
    0%
    1
    6.7%
    0
    0%
    0
    0%
    1
    50%
    59. Secondary Outcome
    Title Number of Participants With Grade >=2 Hypersensitivity Reactions
    Description
    Time Frame Up to day 60

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical Phase 3 Cohort 1: Placebo - Severe Phase 3 Cohort 1: Sarilumab 200mg IV - Severe Phase 3 Cohort 1: Sarilumab 400mg IV - Severe Phase 3 Cohort 1: Placebo - MSOD Phase 3 Cohort 1: Sarilumab 200mg IV - MSOD Phase 3 Cohort 1: Sarilumab 400mg IV - MSOD Phase 3 Cohort 1: Placebo - Immunocompromised Phase 3 Cohort 1: Sarilumab 200mg IV - Immunocompromised Phase 3 Cohort 1: Sarilumab 400mg IV - Immunocompromised Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800 mg IV Phase 3 Cohort 3: Placebo Phase 3 Cohort 3: Sarilumab 800 mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline
    Measure Participants 90 187 180 170 242 338 70 140 137 46 95 92 8 12 15 15 16 6 2
    Count of Participants [Participants]
    0
    0%
    0
    0%
    0
    0%
    1
    0.6%
    1
    0.4%
    0
    0%
    0
    0%
    1
    0.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    60. Secondary Outcome
    Title Number of Participants With Gastrointestinal Perforation
    Description
    Time Frame Up to day 60

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical Phase 3 Cohort 1: Placebo - Severe Phase 3 Cohort 1: Sarilumab 200mg IV - Severe Phase 3 Cohort 1: Sarilumab 400mg IV - Severe Phase 3 Cohort 1: Placebo - MSOD Phase 3 Cohort 1: Sarilumab 200mg IV - MSOD Phase 3 Cohort 1: Sarilumab 400mg IV - MSOD Phase 3 Cohort 1: Placebo - Immunocompromised Phase 3 Cohort 1: Sarilumab 200mg IV - Immunocompromised Phase 3 Cohort 1: Sarilumab 400mg IV - Immunocompromised Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800 mg IV Phase 3 Cohort 3: Placebo Phase 3 Cohort 3: Sarilumab 800 mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline
    Measure Participants 90 187 180 170 242 338 70 140 137 46 95 92 8 12 15 15 16 6 2
    Count of Participants [Participants]
    0
    0%
    1
    0.5%
    0
    0%
    0
    0%
    1
    0.4%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    61. Secondary Outcome
    Title Mean Observed Leukocyte Values Across Study Days (Phase 2)
    Description
    Time Frame Days 1, 4, 15 and 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 population. Only those participants with data available at the specified time points were analyzed.
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 90 187 180
    Day 1
    8.95
    (3.73)
    9.41
    (4.68)
    10.28
    (6.47)
    Day 4
    10.75
    (5.54)
    9.00
    (6.61)
    9.47
    (6.91)
    Day 15
    12.44
    (5.94)
    13.10
    (7.17)
    12.10
    (7.78)
    Day 29
    12.06
    (6.73)
    11.20
    (5.81)
    12.48
    (6.90)
    62. Secondary Outcome
    Title Mean Observed Leukocyte Values Across Study Days (Phase 3)
    Description
    Time Frame Days 1, 4, 15 and 29

    Outcome Measure Data

    Analysis Population Description
    Phase 3 population. Only those participants with data available at the specified time points were analyzed. Phase 3 Cohort 3 data was not summarized due to insufficient sample size.
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical Phase 3 Cohort 1: Placebo - Severe Phase 3 Cohort 1: Sarilumab 200mg IV - Severe Phase 3 Cohort 1: Sarilumab 400mg IV - Severe Phase 3 Cohort 1: Placebo - MSOD Phase 3 Cohort 1: Sarilumab 200mg IV - MSOD Phase 3 Cohort 1: Sarilumab 400mg IV - MSOD Phase 3 Cohort 1: Placebo - Immunocompromised Phase 3 Cohort 1: Sarilumab 200mg IV - Immunocompromised Phase 3 Cohort 1: Sarilumab 400mg IV - Immunocompromised Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800 mg IV Phase 3 Cohort 3: Placebo Phase 3 Cohort 3: Sarilumab 800 mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline
    Measure Participants 170 242 338 70 140 137 46 95 92 8 12 15 15 16 6 2
    Day 1 (Baseline)
    10.18
    (4.57)
    10.51
    (4.83)
    10.52
    (4.442)
    7.83
    (2.97)
    8.16
    (3.42)
    8.38
    (4.06)
    12.01
    (5.57)
    12.98
    (5.72)
    12.35
    (5.78)
    14.26
    (9.99)
    9.13
    (5.112)
    7.20
    (5.28)
    11.52
    (3.55)
    12.13
    (5.27)
    8.80
    (2.14)
    4.80
    (1.84)
    Day 4
    12.11
    (5.49)
    9.47
    (5.77)
    9.19
    (5.82)
    7.93
    (2.87)
    6.76
    (3.92)
    6.89
    (5.10)
    13.53
    (7.44)
    11.62
    (7.05)
    11.25
    (8.42)
    13.48
    (10.88)
    6.44
    (2.68)
    6.50
    (6.36)
    12.15
    (4.87)
    8.30
    (3.87)
    9.96
    (2.92)
    4.70
    (3.54)
    Day 15
    12.03
    (4.68)
    11.26
    (6.79)
    10.47
    (6.28)
    10.58
    (5.86)
    9.68
    (4.88)
    11.18
    (10.52)
    13.97
    (5.57)
    12.73
    (7.25)
    11.90
    (8.88)
    22.45
    (17.05)
    8.12
    (2.75)
    12.84
    (7.21)
    11.70
    (4.81)
    10.68
    (10.76)
    14.45
    (8.12)
    16.40
    (1.84)
    Day 29
    11.90
    (6.00)
    12.17
    (7.45)
    31.35
    (194.41)
    7.81
    (2.66)
    11.56
    (6.67)
    11.72
    (6.28)
    10.22
    (3.62)
    11.15
    (6.84)
    10.50
    (6.44)
    18.30
    (0)
    9.52
    (5.47)
    14.10
    (11.02)
    11.22
    (8.67)
    7.43
    (2.57)
    28.44
    (22.96)
    7.50
    (5.09)
    63. Secondary Outcome
    Title Mean Observed Hemoglobin Values Across Study Days (Phase 2)
    Description
    Time Frame Days 1, 4, 15 and 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 population. Only those participants with data available at the specified time points were analyzed.
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 90 187 180
    Day 1 (Baseline)
    122.53
    (20.65)
    122.19
    (19.75)
    122.75
    (20.27)
    Day 4
    120.30
    (28.23)
    122.79
    (20.44)
    122.61
    (20.83)
    Day 15
    100.04
    (22.39)
    104.11
    (21.88)
    105.85
    (22.67)
    Day 29
    90.48
    (15.30)
    96.00
    (21.36)
    98.20
    (19.20)
    64. Secondary Outcome
    Title Mean Observed Hemoglobin Values Across Study Days (Phase 3)
    Description
    Time Frame Days 1, 4, 15 and 29

    Outcome Measure Data

    Analysis Population Description
    Phase 3 population. Only those participants with data available at the specified time points were analyzed. Phase 3 Cohort 3 data was not summarized due to insufficient sample size
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical Phase 3 Cohort 1: Placebo - Severe Phase 3 Cohort 1: Sarilumab 200mg IV - Severe Phase 3 Cohort 1: Sarilumab 400mg IV - Severe Phase 3 Cohort 1: Placebo - MSOD Phase 3 Cohort 1: Sarilumab 200mg IV - MSOD Phase 3 Cohort 1: Sarilumab 400mg IV - MSOD Phase 3 Cohort 1: Placebo - Immunocompromised Phase 3 Cohort 1: Sarilumab 200mg IV - Immunocompromised Phase 3 Cohort 1: Sarilumab 400mg IV - Immunocompromised Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800 mg IV Phase 3 Cohort 3: Placebo Phase 3 Cohort 3: Sarilumab 800 mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline
    Measure Participants 170 242 338 70 140 137 46 95 92 8 12 15 15 16 6 2
    Day 1 (Baseline)
    117.70
    (19.85)
    121.25
    (20.39)
    121.06
    (19.97)
    127.64
    (15.27)
    124.18
    (20.59)
    124.76
    (20.64)
    114.59
    (19.03)
    110.40
    (22.34)
    104.19
    (19.40)
    121.88
    (24.00)
    120.55
    (18.93)
    99.00
    (22.83)
    111.20
    (19.01)
    115.75
    (21.51)
    122.00
    (17.16)
    111.50
    (33.23)
    Day 4
    112.90
    (20.72)
    121.03
    (20.83)
    120.57
    (21.82)
    123.58
    (16.89)
    125.70
    (20.59)
    125.61
    (20.74)
    101.36
    (16.90)
    106.55
    (21.22)
    102.46
    (20.43)
    114.13
    (15.57)
    118.25
    (21.64)
    97.13
    (22.68)
    103.73
    (19.49)
    114.56
    (17.00)
    115.33
    (16.15)
    113.50
    (38.89)
    Day 15
    99.66
    (20.00)
    104.70
    (22.93)
    107.87
    (23.48)
    112.15
    (21.36)
    106.27
    (20.25)
    113.43
    (27.11)
    91.16
    (15.85)
    95.21
    (18.30)
    90.88
    (18.37)
    106.75
    (28.94)
    111.00
    (21.87)
    91.86
    (19.15)
    92.85
    (16.80)
    109.43
    (15.54)
    103.40
    (20.88)
    101.50
    (14.85)
    Day 29
    84.31
    (15.05)
    91.50
    (18.08)
    96.28
    (19.50)
    86.67
    (17.67)
    99.58
    (22.48)
    88.92
    (22.72)
    85.23
    (10.88)
    88.74
    (13.27)
    88.44
    (15.13)
    135.00
    (0)
    96.00
    (11.27)
    85.20
    (13.68)
    99.40
    (23.03)
    106.29
    (12.59)
    98.50
    (38.89)
    82.50
    (6.36)
    65. Secondary Outcome
    Title Mean Observed Platelet Count Across Study Days (Phase 2)
    Description
    Time Frame Days 1, 4, 15 and 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 population. Only those participants with data available at the specified time points were analyzed.
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 90 187 180
    Day 1 (Baseline)
    241.03
    (102.22)
    249.40
    (100.55)
    261.50
    (94.51)
    Day 4
    314.86
    (129.80)
    304.94
    (117.17)
    319.89
    (116.80)
    Day 15
    351.89
    (155.08)
    264.03
    (116.22)
    257.88
    (118.01)
    Day 29
    313.12
    (148.66)
    306.87
    (119.10)
    312.14
    (147.07)
    66. Secondary Outcome
    Title Mean Observed Platelet Count Across Study Days (Phase 3)
    Description
    Time Frame Days 1, 4, 15 and 29

    Outcome Measure Data

    Analysis Population Description
    Phase 3 population. Only those participants with data available at the specified time points were analyzed. Phase 3 Cohort 3 data was not summarized due to insufficient sample size
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical Phase 3 Cohort 1: Placebo - Severe Phase 3 Cohort 1: Sarilumab 200mg IV - Severe Phase 3 Cohort 1: Sarilumab 400mg IV - Severe Phase 3 Cohort 1: Placebo - MSOD Phase 3 Cohort 1: Sarilumab 200mg IV - MSOD Phase 3 Cohort 1: Sarilumab 400mg IV - MSOD Phase 3 Cohort 1: Placebo - Immunocompromised Phase 3 Cohort 1: Sarilumab 200mg IV - Immunocompromised Phase 3 Cohort 1: Sarilumab 400mg IV - Immunocompromised Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800 mg IV Phase 3 Cohort 3: Placebo Phase 3 Cohort 3: Sarilumab 800 mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline
    Measure Participants 170 242 338 70 140 137 46 95 92 8 12 15 15 16 6 2
    Day 1 (Baseline)
    285.56
    (120.77)
    278.60
    (112.15)
    278.40
    (120.16)
    251.03
    (109.74)
    271.70
    (109.63)
    259.06
    (115.47)
    244.11
    (103.10)
    251.85
    (105.45)
    258.37
    (100.32)
    233.00
    (74.04)
    221.64
    (84.86)
    190.33
    (77.23)
    228.40
    (121.12)
    278.31
    (130.65)
    298.50
    (114.86)
    197.00
    (22.63)
    Day 4
    328.20
    (137.22)
    318.16
    (129.76)
    311.42
    (136.44)
    324.57
    (154.49)
    348.96
    (135.13)
    330.84
    (154.22)
    276.70
    (111.39)
    275.84
    (116.70)
    268.18
    (116.49)
    244.88
    (73.27)
    261.00
    (109.90)
    225.47
    (75.84)
    267.80
    (132.29)
    318.25
    (134.09)
    421.17
    (135.03)
    294.00
    (127.28)
    Day 15
    315.38
    (143.62)
    230.44
    (100.71)
    222.62
    (100.21)
    271.71
    (124.32)
    242.40
    (82.25)
    223.14
    (102.57)
    312.81
    (155.88)
    232.97
    (115.44)
    226.89
    (110.91)
    219.25
    (77.89)
    203.63
    (47.37)
    133.14
    (59.74)
    275.69
    (150.11)
    209.00
    (92.41)
    306.60
    (108.91)
    259.00
    (39.60)
    Day 29
    284.02
    (143.38)
    270.88
    (102.72)
    248.60
    (139.26)
    264.67
    (147.97)
    238.67
    (125.15)
    182.58
    (107.29)
    332.73
    (156.61)
    310.52
    (155.05)
    279.31
    (124.43)
    267.00
    (0)
    281.00
    (130.09)
    181.25
    (53.01)
    265.00
    (70.67)
    235.71
    (100.19)
    272.00
    (26.87)
    373.00
    (367.70)
    67. Secondary Outcome
    Title Mean Observed Total Bilirubin Values Across Study Days (Phase 2)
    Description
    Time Frame Days 1, 4, 15 and 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 Population. Only those participants with data available at the specified time points were analyzed.
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 90 187 180
    Day 1 (Baseline)
    12.07
    (14.20)
    11.96
    (13.59)
    12.24
    (15.77)
    Day 4
    12.44
    (10.90)
    11.87
    (17.12)
    9.89
    (11.10)
    Day 15
    13.75
    (17.63)
    12.43
    (8.69)
    14.16
    (21.94)
    Day 29
    14.00
    (19.84)
    7.87
    (3.44)
    11.40
    (12.23)
    68. Secondary Outcome
    Title Mean Observed Total Bilirubin Across Study Days (Phase 3)
    Description
    Time Frame Days 1, 4, 15 and 29

    Outcome Measure Data

    Analysis Population Description
    Phase 3 population. Only those participants with data available at the specified time points were analyzed. Phase 3 Cohort 3 data was not summarized due to insufficient sample size
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical Phase 3 Cohort 1: Placebo - Severe Phase 3 Cohort 1: Sarilumab 200mg IV - Severe Phase 3 Cohort 1: Sarilumab 400mg IV - Severe Phase 3 Cohort 1: Placebo - MSOD Phase 3 Cohort 1: Sarilumab 200mg IV - MSOD Phase 3 Cohort 1: Sarilumab 400mg IV - MSOD Phase 3 Cohort 1: Placebo - Immunocompromised Phase 3 Cohort 1: Sarilumab 200mg IV - Immunocompromised Phase 3 Cohort 1: Sarilumab 400mg IV - Immunocompromised Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800 mg IV Phase 3 Cohort 3: Placebo Phase 3 Cohort 3: Sarilumab 800 mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline
    Measure Participants 170 242 338 70 140 137 46 95 92 8 12 15 15 16 6 2
    Day 1 (Baseline)
    11.79
    (7.66)
    12.02
    (7.82)
    12.99
    (14.20)
    9.09
    (4.17)
    9.93
    (5.27)
    10.12
    (5.95)
    10.94
    (8.57)
    16.89
    (21.77)
    16.56
    (13.46)
    6.27
    (2.57)
    10.10
    (9.90)
    7.30
    (4.77)
    10.79
    (7.47)
    9.92
    (5.93)
    9.98
    (1.68)
    9.41
    (1.21)
    Day 4
    13.11
    (13.11)
    10.10
    (6.39)
    10.21
    (8.61)
    9.53
    (4.67)
    8.45
    (5.43)
    8.38
    (4.16)
    14.57
    (14.93)
    10.94
    (10.45)
    13.98
    (11.00)
    7.98
    (6.18)
    10.26
    (8.12)
    6.96
    (3.11)
    12.43
    (5.19)
    7.70
    (5.15)
    11.40
    (4.55)
    9.41
    (3.63)
    Day 15
    16.47
    (37.13)
    11.66
    (8.09)
    15.60
    (48.78)
    8.66
    (2.54)
    11.07
    (7.15)
    19.37
    (47.14)
    13.20
    (11.02)
    10.69
    (7.93)
    14.26
    (18.85)
    19.24
    (10.76)
    16.37
    (24.60)
    8.55
    (2.61)
    23.09
    (45.49)
    10.97
    (3.53)
    10.26
    (4.52)
    11.97
    (2.42)
    Day 29
    11.66
    (11.00)
    11.74
    (13.86)
    19.24
    (38.66)
    9.69
    (0.99)
    25.48
    (38.28)
    31.19
    (71.38)
    9.69
    (9.13)
    9.44
    (9.44)
    10.54
    (8.19)
    13.68
    (0)
    3.42
    (0)
    8.89
    (3.71)
    4.27
    (1.21)
    6.56
    (2.52)
    13.68
    (14.51)
    7.70
    (3.63)
    69. Secondary Outcome
    Title Mean Observed Aspartate Aminotransferase Values Across Study Days (Phase 2)
    Description
    Time Frame Days 1, 4, 15 and 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 Population. Only those participants with data available at the specified time points were analyzed.
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 90 187 180
    Day 1 (Baseline)
    58.58
    (32.40)
    57.88
    (33.35)
    60.39
    (36.85)
    Day 4
    62.52
    (61.41)
    90.01
    (127.42)
    78.34
    (63.75)
    Day 15
    42.12
    (25.17)
    188.65
    (941.96)
    88.96
    (329.04)
    Day 29
    76.00
    (82.78)
    40.69
    (35.70)
    100.05
    (337.72)
    70. Secondary Outcome
    Title Mean Observed Aspartate Aminotransferase Values Across Study Days (Phase 3)
    Description
    Time Frame Days 1, 4, 15 and 29

    Outcome Measure Data

    Analysis Population Description
    Phase 3 population. Only those participants with data available at the specified time points were analyzed. Phase 3 Cohort 3 data was not summarized due to insufficient sample size
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical Phase 3 Cohort 1: Placebo - Severe Phase 3 Cohort 1: Sarilumab 200mg IV - Severe Phase 3 Cohort 1: Sarilumab 400mg IV - Severe Phase 3 Cohort 1: Placebo - MSOD Phase 3 Cohort 1: Sarilumab 200mg IV - MSOD Phase 3 Cohort 1: Sarilumab 400mg IV - MSOD Phase 3 Cohort 1: Placebo - Immunocompromised Phase 3 Cohort 1: Sarilumab 200mg IV - Immunocompromised Phase 3 Cohort 1: Sarilumab 400mg IV - Immunocompromised Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800 mg IV Phase 3 Cohort 3: Placebo Phase 3 Cohort 3: Sarilumab 800 mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD)[vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD)[vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD)[vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline
    Measure Participants 170 242 338 70 140 137 46 95 92 8 12 15 15 16 6 2
    Day 1 (Baseline)
    58.54
    (33.67)
    54.73
    (35.99)
    60.61
    (39.15)
    51.54
    (28.35)
    58.58
    (45.19)
    47.80
    (29.38)
    61.13
    (38.23)
    77.66
    (163.34)
    57.68
    (36.02)
    47.00
    (37.44)
    47.36
    (24.52)
    35.47
    (22.96)
    58.77
    (42.03)
    58.33
    (27.48)
    114.00
    (134.17)
    36.50
    (3.54)
    Day 4
    60.21
    (74.93)
    69.30
    (65.10)
    78.29
    (108.57)
    52.79
    (39.90)
    66.47
    (63.95)
    76.77
    (178.97)
    65.39
    (52.27)
    94.76
    (136.93)
    124.83
    (270.78)
    58.00
    (69.65)
    51.33
    (33.72)
    52.93
    (48.68)
    76.73
    (35.24)
    75.88
    (51.15)
    74.50
    (65.31)
    32.50
    (19.09)
    Day 15
    62.95
    (131.49)
    72.27
    (232.21)
    75.08
    (162.60)
    38.73
    (20.81)
    73.42
    (152.57)
    126.70
    (312.36)
    50.00
    (37.36)
    49.89
    (46.50)
    98.84
    (276.99)
    128.25
    (180.12)
    45.29
    (26.30)
    52.29
    (43.10)
    33.17
    (9.68)
    64.08
    (58.97)
    40.00
    (41.87)
    15.00
    (4.24)
    Day 29
    52.76
    (102.66)
    163.83
    (817.08)
    363.69
    (2565.77)
    80.33
    (65.90)
    347.60
    (982.89)
    72.17
    (86.39)
    35.24
    (21.51)
    40.07
    (25.67)
    38.19
    (29.82)
    25.00
    (0)
    20.00
    (0)
    31.20
    (16.69)
    25.50
    (13.44)
    46.67
    (39.87)
    69.00
    (57.98)
    46.00
    (42.43)
    71. Secondary Outcome
    Title Mean Observed Alanine Aminotransferase Values Across Study Days (Phase 2)
    Description
    Time Frame Days 1, 4, 15 and 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 Population. Only those participants with data available at the specified time points were analyzed.
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 90 187 180
    Day 1 (Baseline)
    47.93
    (34.75)
    50.25
    (36.69)
    48.25
    (30.38)
    Day 4
    54.34
    (42.15)
    86.08
    (148.46)
    74.20
    (78.45)
    Day 15
    55.00
    (37.75)
    106.17
    (282.61)
    121.58
    (507.41)
    Day 29
    94.30
    (112.36)
    58.63
    (48.92)
    64.82
    (78.90)
    72. Secondary Outcome
    Title Mean Observed Alanine Aminotransferase Values Across Study Days (Phase 3)
    Description
    Time Frame Days 1, 4, 15 and 29

    Outcome Measure Data

    Analysis Population Description
    Phase 3 population. Only those participants with data available at the specified time points were analyzed. Phase 3 Cohort 3 data was not summarized due to insufficient sample size
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical Phase 3 Cohort 1: Placebo - Severe Phase 3 Cohort 1: Sarilumab 200mg IV - Severe Phase 3 Cohort 1: Sarilumab 400mg IV - Severe Phase 3 Cohort 1: Placebo - MSOD Phase 3 Cohort 1: Sarilumab 200mg IV - MSOD Phase 3 Cohort 1: Sarilumab 400mg IV - MSOD Phase 3 Cohort 1: Placebo - Immunocompromised Phase 3 Cohort 1: Sarilumab 200mg IV - Immunocompromised Phase 3 Cohort 1: Sarilumab 400mg IV - Immunocompromised Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800 mg IV Phase 3 Cohort 3: Placebo Phase 3 Cohort 3: Sarilumab 800 mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline
    Measure Participants 170 242 338 70 140 137 46 95 92 8 12 15 15 16 6 2
    Day 1 (Baseline)
    51.69
    (37.36)
    51.08
    (35.87)
    52.15
    (36.66)
    46.69
    (34.09)
    54.22
    (42.27)
    49.43
    (39.98)
    45.00
    (35.07)
    59.13
    (96.74)
    41.75
    (29.42)
    33.50
    (18.45)
    43.00
    (31.81)
    22.27
    (25.57)
    46.77
    (31.49)
    45.33
    (40.77)
    103.33
    (153.15)
    33.50
    (30.41)
    Day 4
    73.45
    (139.06)
    72.32
    (60.25)
    74.62
    (77.09)
    59.38
    (51.04)
    68.69
    (51.45)
    86.13
    (146.92)
    52.22
    (52.86)
    69.75
    (102.66)
    84.68
    (152.72)
    40.86
    (26.62)
    45.17
    (23.35)
    38.50
    (45.66)
    62.27
    (33.29)
    53.06
    (44.57)
    103.67
    (174.35)
    32.00
    (28.28)
    Day 15
    71.09
    (71.11)
    79.98
    (131.21)
    93.82
    (155.98)
    52.60
    (48.06)
    97.73
    (205.87)
    101.00
    (156.42)
    62.11
    (42.15)
    64.80
    (68.11)
    98.31
    (163.08)
    257.25
    (454.57)
    66.14
    (51.89)
    47.57
    (53.53)
    45.83
    (24.52)
    85.75
    (104.56)
    24.33
    (7.51)
    14.00
    (4.24)
    Day 29
    66.71
    (107.24)
    86.04
    (155.72)
    155.63
    (759.34)
    60.00
    (36.37)
    127.30
    (173.38)
    88.17
    (127.32)
    46.24
    (48.87)
    46.85
    (28.14)
    48.51
    (39.44)
    17.00
    (0)
    39.00
    (0)
    36.00
    (32.99)
    25.50
    (0.71)
    58.33
    (33.66)
    48.00
    (12.73)
    83.50
    (85.56)
    73. Secondary Outcome
    Title Mean Observed Creatinine Values Across Study Days (Phase 2)
    Description
    Time Frame Days 1, 4, 15 and 29

    Outcome Measure Data

    Analysis Population Description
    Phase 2 population. Only those participants with data available at the specified time points were analyzed.
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment
    Measure Participants 90 187 180
    Day 1 (Baseline)
    129.81
    (142.13)
    137.20
    (148.58)
    158.18
    (242.13)
    Day 4
    153.12
    (184.77)
    151.86
    (163.45)
    164.62
    (246.69)
    Day 15
    188.56
    (260.81)
    168.74
    (201.28)
    155.23
    (163.50)
    Day 29
    147.52
    (138.14)
    138.02
    (121.95)
    118.56
    (133.25)
    74. Secondary Outcome
    Title Mean Observed Creatinine Values Across Study Days (Phase 3)
    Description
    Time Frame Days 1, 4, 15 and 29

    Outcome Measure Data

    Analysis Population Description
    Phase 3 population. Only those participants with data available at the specified time points were analyzed. Phase 3 Cohort 3 data was not summarized due to insufficient sample size
    Arm/Group Title Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical Phase 3 Cohort 1: Placebo - Severe Phase 3 Cohort 1: Sarilumab 200mg IV - Severe Phase 3 Cohort 1: Sarilumab 400mg IV - Severe Phase 3 Cohort 1: Placebo - MSOD Phase 3 Cohort 1: Sarilumab 200mg IV - MSOD Phase 3 Cohort 1: Sarilumab 400mg IV - MSOD Phase 3 Cohort 1: Placebo - Immunocompromised Phase 3 Cohort 1: Sarilumab 200mg IV - Immunocompromised Phase 3 Cohort 1: Sarilumab 400mg IV - Immunocompromised Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800 mg IV Phase 3 Cohort 3: Placebo Phase 3 Cohort 3: Sarilumab 800 mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline
    Measure Participants 170 242 338 70 140 137 46 95 92 8 12 15 15 16 6 2
    Day 1 (Baseline)
    122.64
    (145.57)
    141.97
    (187.40)
    121.75
    (132.43)
    109.14
    (196.52)
    174.92
    (802.76)
    111.63
    (168.83)
    187.93
    (232.11)
    308.63
    (308.42)
    280.83
    (280.30)
    259.01
    (401.63)
    265.36
    (396.16)
    401.87
    (294.63)
    103.19
    (74.60)
    78.79
    (30.71)
    108.73
    (92.72)
    497.25
    (621.96)
    Day 4
    133.77
    (144.10)
    129.08
    (145.08)
    128.56
    (127.48)
    93.23
    (151.97)
    101.45
    (129.88)
    113.30
    (152.19)
    176.80
    (160.17)
    314.53
    (352.59)
    281.92
    (310.48)
    267.96
    (479.59)
    205.38
    (249.38)
    395.09
    (246.34)
    121.40
    (84.33)
    99.28
    (96.74)
    83.24
    (62.60)
    458.80
    (576.33)
    Day 15
    151.06
    (175.53)
    136.98
    (149.03)
    120.96
    (134.39)
    151.11
    (284.59)
    175.09
    (243.54)
    111.99
    (97.29)
    160.94
    (198.07)
    179.87
    (183.06)
    170.10
    (198.20)
    142.32
    (115.06)
    137.46
    (99.29)
    270.39
    (176.43)
    116.96
    (92.34)
    86.06
    (64.78)
    136.49
    (110.96)
    311.61
    (396.93)
    Day 29
    133.14
    (140.37)
    124.97
    (124.62)
    100.02
    (107.10)
    122.88
    (161.56)
    205.17
    (269.33)
    143.62
    (98.50)
    128.74
    (191.15)
    125.21
    (128.22)
    197.65
    (655.38)
    80.44
    (0)
    116.69
    (32.20)
    195.01
    (108.79)
    55.69
    (15.14)
    78.30
    (40.12)
    65.86
    (11.88)
    276.25
    (346.92)

    Adverse Events

    Time Frame From first dose of study drug to Day 60
    Adverse Event Reporting Description
    Arm/Group Title Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical Phase 3 Cohort 1: Placebo - Severe Phase 3 Cohort 1: Sarilumab 200mg IV - Severe Phase 3 Cohort 1: Sarilumab 400mg IV - Severe Phase 3 Cohort 1: Placebo - MSOD Phase 3 Cohort 1: Sarilumab 200 mg IV - MSOD Phase 3 Cohort 1: Sarilumab 400 mg IV - MSOD Phase 3 Cohort 1: Placebo - Immunocompromised Phase 3 Cohort 1: Sarilumab 200 mg IV - Immunocompromised Phase 3 Cohort 1: Sarilumab 400 mg IV - Immunocompromised Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800 mg IV Phase 3 Cohort 3: Placebo Phase 3 Cohort 3: Sarilumab 800 mg IV
    Arm/Group Description Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and one of the following disease strata: Severe disease Critical disease Multi-system organ dysfunction/Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Critical disease (suppl. O2 by non-rebreather/high-flow cannula or invasive/non-invasive ventilation or treatment in ICU) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Severe disease (suppl. O2 by nasal cannula, face mask, or similar O2 delivery device) Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Multi-system organ dysfunction (MSOD) [vasopressors, extracorporeal life support, or renal replacement therapy] Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection and in the following disease strata: -Immunocompromised or on immunosuppressive treatment Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring mechanical ventilation due to COVID-19 Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline Hospitalized with SARS-CoV-2 infection requiring high-Intensity oxygen therapy without Mechanical Ventilation at baseline
    All Cause Mortality
    Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical Phase 3 Cohort 1: Placebo - Severe Phase 3 Cohort 1: Sarilumab 200mg IV - Severe Phase 3 Cohort 1: Sarilumab 400mg IV - Severe Phase 3 Cohort 1: Placebo - MSOD Phase 3 Cohort 1: Sarilumab 200 mg IV - MSOD Phase 3 Cohort 1: Sarilumab 400 mg IV - MSOD Phase 3 Cohort 1: Placebo - Immunocompromised Phase 3 Cohort 1: Sarilumab 200 mg IV - Immunocompromised Phase 3 Cohort 1: Sarilumab 400 mg IV - Immunocompromised Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800 mg IV Phase 3 Cohort 3: Placebo Phase 3 Cohort 3: Sarilumab 800 mg IV
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 24/90 (26.7%) 60/187 (32.1%) 49/180 (27.2%) 59/170 (34.7%) 70/242 (28.9%) 114/338 (33.7%) 9/70 (12.9%) 12/140 (8.6%) 21/137 (15.3%) 16/46 (34.8%) 40/95 (42.1%) 40/92 (43.5%) 3/8 (37.5%) 4/12 (33.3%) 6/15 (40%) 4/15 (26.7%) 3/16 (18.8%) 1/6 (16.7%) 0/2 (0%)
    Serious Adverse Events
    Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical Phase 3 Cohort 1: Placebo - Severe Phase 3 Cohort 1: Sarilumab 200mg IV - Severe Phase 3 Cohort 1: Sarilumab 400mg IV - Severe Phase 3 Cohort 1: Placebo - MSOD Phase 3 Cohort 1: Sarilumab 200 mg IV - MSOD Phase 3 Cohort 1: Sarilumab 400 mg IV - MSOD Phase 3 Cohort 1: Placebo - Immunocompromised Phase 3 Cohort 1: Sarilumab 200 mg IV - Immunocompromised Phase 3 Cohort 1: Sarilumab 400 mg IV - Immunocompromised Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800 mg IV Phase 3 Cohort 3: Placebo Phase 3 Cohort 3: Sarilumab 800 mg IV
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 39/90 (43.3%) 90/187 (48.1%) 84/180 (46.7%) 89/170 (52.4%) 119/242 (49.2%) 183/338 (54.1%) 11/70 (15.7%) 23/140 (16.4%) 30/137 (21.9%) 27/46 (58.7%) 67/95 (70.5%) 58/92 (63%) 3/8 (37.5%) 6/12 (50%) 9/15 (60%) 10/15 (66.7%) 5/16 (31.3%) 1/6 (16.7%) 1/2 (50%)
    Blood and lymphatic system disorders
    Anaemia 1/90 (1.1%) 1 1/187 (0.5%) 1 4/180 (2.2%) 5 4/170 (2.4%) 4 3/242 (1.2%) 3 4/338 (1.2%) 4 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 1/15 (6.7%) 1 3/15 (20%) 3 1/16 (6.3%) 1 0/6 (0%) 0 0/2 (0%) 0
    Anaemia macrocytic 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Blood loss anaemia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Disseminated intravascular coagulation 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Heparin-induced thrombocytopenia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Immune thrombocytopenia 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Leukopenia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 1/137 (0.7%) 1 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Neutropenia 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 2/242 (0.8%) 2 0/338 (0%) 0 0/70 (0%) 0 1/140 (0.7%) 1 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Normocytic anaemia 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pancytopenia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Thrombocytopenia 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 1/170 (0.6%) 1 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Thrombocytosis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Cardiac disorders
    Cardio-respiratory arrest 6/90 (6.7%) 6 11/187 (5.9%) 11 8/180 (4.4%) 8 1/170 (0.6%) 1 3/242 (1.2%) 3 2/338 (0.6%) 2 2/70 (2.9%) 2 0/140 (0%) 0 2/137 (1.5%) 2 0/46 (0%) 0 0/95 (0%) 0 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 1/16 (6.3%) 1 0/6 (0%) 0 0/2 (0%) 0
    Cardiac arrest 3/90 (3.3%) 3 9/187 (4.8%) 9 16/180 (8.9%) 16 7/170 (4.1%) 7 7/242 (2.9%) 8 25/338 (7.4%) 26 2/70 (2.9%) 2 4/140 (2.9%) 4 3/137 (2.2%) 3 6/46 (13%) 6 9/95 (9.5%) 9 9/92 (9.8%) 9 0/8 (0%) 0 0/12 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Atrial fibrillation 1/90 (1.1%) 1 1/187 (0.5%) 1 3/180 (1.7%) 3 3/170 (1.8%) 3 3/242 (1.2%) 3 4/338 (1.2%) 4 0/70 (0%) 0 1/140 (0.7%) 1 0/137 (0%) 0 0/46 (0%) 0 2/95 (2.1%) 2 3/92 (3.3%) 3 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 1/6 (16.7%) 1 0/2 (0%) 0
    Right ventricular failure 1/90 (1.1%) 1 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Tachycardia 1/90 (1.1%) 1 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Acute myocardial infarction 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 3/338 (0.9%) 3 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 3/92 (3.3%) 3 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Angina pectoris 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Atrial flutter 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 1/242 (0.4%) 1 2/338 (0.6%) 2 0/70 (0%) 0 0/140 (0%) 0 1/137 (0.7%) 1 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Bradycardia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 1/242 (0.4%) 1 0/338 (0%) 0 1/70 (1.4%) 1 0/140 (0%) 0 1/137 (0.7%) 1 0/46 (0%) 0 1/95 (1.1%) 1 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Cardiac failure 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Cardiac failure congestive 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Cardiac ventricular thrombosis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Cardiogenic shock 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 3/338 (0.9%) 3 0/70 (0%) 0 0/140 (0%) 0 1/137 (0.7%) 1 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 1/16 (6.3%) 1 0/6 (0%) 0 0/2 (0%) 0
    Cardiopulmonary failure 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Congestive cardiomyopathy 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Myocardial infarction 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 1/140 (0.7%) 1 1/137 (0.7%) 1 0/46 (0%) 0 0/95 (0%) 0 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pulseless electrical activity 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 3/170 (1.8%) 3 1/242 (0.4%) 1 2/338 (0.6%) 2 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 1/15 (6.7%) 2 0/15 (0%) 0 0/16 (0%) 0 1/6 (16.7%) 1 0/2 (0%) 0
    Right ventricular dysfunction 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Stress cardiomyopathy 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Supraventricular tachycardia 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 2/95 (2.1%) 2 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Torsade de pointes 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Ventricular fibrillation 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Ventricular tachycardia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 2/170 (1.2%) 2 1/242 (0.4%) 1 2/338 (0.6%) 2 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Congenital, familial and genetic disorders
    Antithrombin III deficiency 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage 1/90 (1.1%) 1 0/187 (0%) 0 3/180 (1.7%) 3 2/170 (1.2%) 2 3/242 (1.2%) 3 5/338 (1.5%) 5 0/70 (0%) 0 1/140 (0.7%) 1 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Abdominal pain lower 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 1/137 (0.7%) 1 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Abdominal wall haematoma 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Dysphagia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Gastric ulcer 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Gastritis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Gastrointestinal ischaemia 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Gastrointestinal necrosis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Haematemesis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Haematochezia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Intestinal ischaemia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Intestinal perforation 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 2 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Large intestine perforation 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Lower gastrointestinal haemorrhage 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Melaena 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Oesophageal ulcer haemorrhage 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 1/137 (0.7%) 1 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pancreatitis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pancreatitis acute 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Rectal haemorrhage 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Retroperitoneal haematoma 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Retroperitoneal haemorrhage 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 2/242 (0.8%) 2 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 2/95 (2.1%) 2 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Upper gastrointestinal haemorrhage 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    General disorders
    Multiple organ dysfunction syndrome 1/90 (1.1%) 1 2/187 (1.1%) 2 4/180 (2.2%) 4 4/170 (2.4%) 4 4/242 (1.7%) 4 10/338 (3%) 11 0/70 (0%) 0 1/140 (0.7%) 1 4/137 (2.9%) 5 1/46 (2.2%) 1 3/95 (3.2%) 3 4/92 (4.3%) 4 0/8 (0%) 0 0/12 (0%) 0 2/15 (13.3%) 2 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Asthenia 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Chest pain 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 1/70 (1.4%) 1 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Death 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 1/137 (0.7%) 1 1/46 (2.2%) 1 0/95 (0%) 0 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Device related thrombosis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Non-cardiac chest pain 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pneumatosis 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pyrexia 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Systemic inflammatory response syndrome 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 1/70 (1.4%) 1 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Hepatobiliary disorders
    Bile duct obstruction 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Cholecystitis 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 2/242 (0.8%) 2 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Hepatic failure 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Immune system disorders
    Cytokine storm 1/90 (1.1%) 1 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Infections and infestations
    COVID-19 3/90 (3.3%) 3 13/187 (7%) 13 5/180 (2.8%) 5 15/170 (8.8%) 15 19/242 (7.9%) 19 23/338 (6.8%) 23 0/70 (0%) 0 2/140 (1.4%) 2 5/137 (3.6%) 5 5/46 (10.9%) 5 12/95 (12.6%) 12 9/92 (9.8%) 10 0/8 (0%) 0 2/12 (16.7%) 2 0/15 (0%) 0 1/15 (6.7%) 1 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Staphylococcal infection 3/90 (3.3%) 4 0/187 (0%) 0 4/180 (2.2%) 4 2/170 (1.2%) 2 1/242 (0.4%) 1 3/338 (0.9%) 3 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Bacteraemia 2/90 (2.2%) 2 2/187 (1.1%) 2 3/180 (1.7%) 3 0/170 (0%) 0 3/242 (1.2%) 3 3/338 (0.9%) 3 0/70 (0%) 0 1/140 (0.7%) 1 2/137 (1.5%) 2 1/46 (2.2%) 1 2/95 (2.1%) 2 2/92 (2.2%) 2 0/8 (0%) 0 0/12 (0%) 0 1/15 (6.7%) 1 1/15 (6.7%) 1 1/16 (6.3%) 1 0/6 (0%) 0 0/2 (0%) 0
    Bacterial infection 1/90 (1.1%) 1 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 1/242 (0.4%) 1 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Bacterial tracheitis 1/90 (1.1%) 1 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Endocarditis 1/90 (1.1%) 1 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Escherichia infection 1/90 (1.1%) 1 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pneumonia 1/90 (1.1%) 1 0/187 (0%) 0 4/180 (2.2%) 4 5/170 (2.9%) 5 4/242 (1.7%) 4 5/338 (1.5%) 5 1/70 (1.4%) 1 0/140 (0%) 0 1/137 (0.7%) 1 1/46 (2.2%) 1 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pneumonia klebsiella 1/90 (1.1%) 1 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 2/242 (0.8%) 2 2/338 (0.6%) 2 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 2/46 (4.3%) 2 3/95 (3.2%) 4 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Sepsis 1/90 (1.1%) 1 3/187 (1.6%) 3 0/180 (0%) 0 2/170 (1.2%) 2 3/242 (1.2%) 3 8/338 (2.4%) 8 0/70 (0%) 0 1/140 (0.7%) 1 1/137 (0.7%) 1 0/46 (0%) 0 4/95 (4.2%) 4 2/92 (2.2%) 2 0/8 (0%) 0 0/12 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Septic shock 1/90 (1.1%) 1 4/187 (2.1%) 4 2/180 (1.1%) 2 9/170 (5.3%) 10 6/242 (2.5%) 6 12/338 (3.6%) 12 0/70 (0%) 0 1/140 (0.7%) 1 2/137 (1.5%) 2 0/46 (0%) 0 4/95 (4.2%) 4 5/92 (5.4%) 5 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 2/16 (12.5%) 2 1/6 (16.7%) 2 0/2 (0%) 0
    Urinary tract infection 1/90 (1.1%) 1 0/187 (0%) 0 1/180 (0.6%) 1 1/170 (0.6%) 1 3/242 (1.2%) 3 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Achromobacter infection 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Acute sinusitis 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Appendicitis 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Arthritis bacterial 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 1/70 (1.4%) 1 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Bacterial sepsis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Bacteriuria 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Bronchitis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    COVID-19 pneumonia 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 4/170 (2.4%) 4 3/242 (1.2%) 3 5/338 (1.5%) 5 2/70 (2.9%) 2 0/140 (0%) 0 0/137 (0%) 0 1/46 (2.2%) 1 2/95 (2.1%) 2 3/92 (3.3%) 3 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 2/15 (13.3%) 2 1/16 (6.3%) 1 0/6 (0%) 0 0/2 (0%) 0
    Candida infection 0/90 (0%) 0 2/187 (1.1%) 2 0/180 (0%) 0 1/170 (0.6%) 1 1/242 (0.4%) 1 2/338 (0.6%) 3 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Clostridium difficile colitis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Clostridium difficile infection 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Coronavirus infection 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 4/242 (1.7%) 4 2/338 (0.6%) 2 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 1/46 (2.2%) 1 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Corynebacterium infection 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Enterobacter bacteraemia 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Enterobacter infection 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 3/338 (0.9%) 3 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Enterobacter pneumonia 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 2/338 (0.6%) 2 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 1/46 (2.2%) 1 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Enterococcal bacteraemia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 2 3/242 (1.2%) 3 2/338 (0.6%) 2 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Enterococcal infection 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 3/170 (1.8%) 3 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 1/137 (0.7%) 1 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Enterococcal sepsis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Escherichia bacteraemia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Escherichia urinary tract infection 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Fungaemia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 3/170 (1.8%) 3 1/242 (0.4%) 1 2/338 (0.6%) 2 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Fungal infection 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Fungal sepsis 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Gangrene 0/90 (0%) 0 1/187 (0.5%) 1 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Gastroenteritis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Groin abscess 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Haemophilus infection 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 2/242 (0.8%) 2 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Histoplasmosis 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Infected skin ulcer 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Klebsiella bacteraemia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 2/338 (0.6%) 2 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Klebsiella infection 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 2/338 (0.6%) 2 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 1/12 (8.3%) 1 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Klebsiella sepsis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Lower respiratory tract infection bacterial 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Lung abscess 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Morganella infection 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Oropharyngeal candidiasis 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pneumonia acinetobacter 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pneumonia bacterial 0/90 (0%) 0 1/187 (0.5%) 1 3/180 (1.7%) 3 0/170 (0%) 0 3/242 (1.2%) 3 3/338 (0.9%) 3 0/70 (0%) 0 0/140 (0%) 0 1/137 (0.7%) 1 0/46 (0%) 0 1/95 (1.1%) 1 2/92 (2.2%) 2 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 2/15 (13.3%) 2 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pneumonia escherichia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pneumonia proteus 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pneumonia pseudomonal 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 1/170 (0.6%) 1 4/242 (1.7%) 4 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 1/46 (2.2%) 1 1/95 (1.1%) 1 2/92 (2.2%) 2 0/8 (0%) 0 1/12 (8.3%) 1 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pneumonia serratia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pneumonia staphylococcal 0/90 (0%) 0 3/187 (1.6%) 3 0/180 (0%) 0 2/170 (1.2%) 2 2/242 (0.8%) 2 3/338 (0.9%) 3 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pseudomonal bacteraemia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 2/242 (0.8%) 2 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pseudomonas infection 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 2/170 (1.2%) 3 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pyelonephritis 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Serratia infection 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 1/137 (0.7%) 1 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Spinal cord infection 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 1/140 (0.7%) 1 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Staphylococcal bacteraemia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 2/242 (0.8%) 2 3/338 (0.9%) 3 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 2/92 (2.2%) 2 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Staphylococcal sepsis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Stoma site cellulitis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Streptococcal bacteraemia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Urinary tract candidiasis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Urinary tract infection enterococcal 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 1/70 (1.4%) 1 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Urinary tract infection pseudomonal 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Viral cardiomyopathy 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Injury, poisoning and procedural complications
    Infusion related reaction 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Post procedural haemorrhage 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Procedural pneumothorax 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 1/8 (12.5%) 1 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Subarachnoid haemorrhage 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Subdural haematoma 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Tracheal haemorrhage 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 1/140 (0.7%) 1 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Investigations
    Alanine aminotransferase increased 2/90 (2.2%) 2 2/187 (1.1%) 2 4/180 (2.2%) 4 2/170 (1.2%) 2 4/242 (1.7%) 4 4/338 (1.2%) 4 0/70 (0%) 0 0/140 (0%) 0 3/137 (2.2%) 3 0/46 (0%) 0 1/95 (1.1%) 1 3/92 (3.3%) 3 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Aspartate aminotransferase increased 1/90 (1.1%) 1 2/187 (1.1%) 2 3/180 (1.7%) 3 4/170 (2.4%) 4 4/242 (1.7%) 4 2/338 (0.6%) 2 0/70 (0%) 0 2/140 (1.4%) 2 3/137 (2.2%) 3 0/46 (0%) 0 1/95 (1.1%) 1 4/92 (4.3%) 4 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Klebsiella test positive 1/90 (1.1%) 1 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Transaminases increased 1/90 (1.1%) 1 6/187 (3.2%) 6 1/180 (0.6%) 1 1/170 (0.6%) 1 3/242 (1.2%) 3 4/338 (1.2%) 5 0/70 (0%) 0 0/140 (0%) 0 1/137 (0.7%) 1 2/46 (4.3%) 2 3/95 (3.2%) 3 2/92 (2.2%) 2 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 1/16 (6.3%) 1 0/6 (0%) 0 0/2 (0%) 0
    Anticoagulation drug level below therapeutic 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Blood potassium increased 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 1/137 (0.7%) 1 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Body temperature increased 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Electrocardiogram QT prolonged 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 1/46 (2.2%) 1 1/95 (1.1%) 1 2/92 (2.2%) 2 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Electrocardiogram change 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Enterobacter test positive 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Enterococcus test positive 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Hepatic enzyme increased 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Liver function test abnormal 0/90 (0%) 0 1/187 (0.5%) 1 1/180 (0.6%) 1 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Liver function test increased 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 2/170 (1.2%) 2 0/242 (0%) 0 2/338 (0.6%) 2 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 2/92 (2.2%) 2 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Oxygen saturation decreased 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Platelet count increased 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Metabolism and nutrition disorders
    Hypernatraemia 1/90 (1.1%) 1 0/187 (0%) 0 2/180 (1.1%) 2 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 1/46 (2.2%) 1 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Hypoglycaemia 1/90 (1.1%) 1 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Hypokalaemia 1/90 (1.1%) 1 2/187 (1.1%) 2 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 1/46 (2.2%) 1 2/95 (2.1%) 2 2/92 (2.2%) 2 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Lactic acidosis 1/90 (1.1%) 1 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 4/338 (1.2%) 4 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Acidosis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Diabetic ketoacidosis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 1/137 (0.7%) 1 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Fluid overload 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Hyperglycaemia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Hyperkalaemia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Hypertriglyceridaemia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Hypervolaemia 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Hypocalcaemia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Hyponatraemia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Metabolic acidosis 0/90 (0%) 0 2/187 (1.1%) 2 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 1/92 (1.1%) 1 0/8 (0%) 0 1/12 (8.3%) 1 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Metabolic alkalosis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 1/46 (2.2%) 1 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Musculoskeletal and connective tissue disorders
    Chest wall haematoma 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Muscular weakness 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Neck pain 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 1/70 (1.4%) 1 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Rhabdomyolysis 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Plasma cell myeloma 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 1/140 (0.7%) 1 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Nervous system disorders
    Cerebrovascular accident 2/90 (2.2%) 2 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 2/338 (0.6%) 2 0/70 (0%) 0 0/140 (0%) 0 2/137 (1.5%) 2 0/46 (0%) 0 0/95 (0%) 0 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Encephalopathy 2/90 (2.2%) 2 2/187 (1.1%) 2 1/180 (0.6%) 1 2/170 (1.2%) 2 1/242 (0.4%) 1 1/338 (0.3%) 1 0/70 (0%) 0 1/140 (0.7%) 1 0/137 (0%) 0 0/46 (0%) 0 2/95 (2.1%) 2 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Depressed level of consciousness 1/90 (1.1%) 1 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Seizure 1/90 (1.1%) 1 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 2/338 (0.6%) 2 1/70 (1.4%) 1 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Alcoholic seizure 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 1/16 (6.3%) 1 0/6 (0%) 0 0/2 (0%) 0
    Brachial plexopathy 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 3/338 (0.9%) 3 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Brain oedema 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Cerebral artery embolism 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Cerebral artery occlusion 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Cerebral artery stenosis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Cerebral haemorrhage 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 2/242 (0.8%) 3 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Cerebral infarction 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 2/338 (0.6%) 2 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Cubital tunnel syndrome 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Dementia Alzheimer's type 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Encephalitis haemorrhagic 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Haemorrhage intracranial 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Intensive care unit acquired weakness 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Intraventricular haemorrhage 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Ischaemic stroke 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 1/140 (0.7%) 1 1/137 (0.7%) 1 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Lethargy 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 2/95 (2.1%) 2 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Metabolic encephalopathy 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Neurological symptom 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Presyncope 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 1/140 (0.7%) 1 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Seizure like phenomena 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Subarachnoid haemorrhage 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 1/242 (0.4%) 1 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Transient ischaemic attack 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 1/46 (2.2%) 1 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Tremor 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Product Issues
    Device dislocation 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Psychiatric disorders
    Agitation 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Alcohol withdrawal syndrome 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Delirium 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Mental status changes 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 1/46 (2.2%) 1 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Neuropsychiatric symptoms 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 5/90 (5.6%) 6 9/187 (4.8%) 9 9/180 (5%) 9 10/170 (5.9%) 10 12/242 (5%) 12 10/338 (3%) 10 0/70 (0%) 0 0/140 (0%) 0 1/137 (0.7%) 1 1/46 (2.2%) 1 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 2/15 (13.3%) 2 0/16 (0%) 0 1/6 (16.7%) 1 0/2 (0%) 0
    Renal failure 1/90 (1.1%) 1 4/187 (2.1%) 4 2/180 (1.1%) 2 1/170 (0.6%) 1 4/242 (1.7%) 4 2/338 (0.6%) 2 0/70 (0%) 0 0/140 (0%) 0 2/137 (1.5%) 2 0/46 (0%) 0 3/95 (3.2%) 3 2/92 (2.2%) 2 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Haematuria 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Nephritis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 1/137 (0.7%) 1 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Renal impairment 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 1/170 (0.6%) 1 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Renal tubular necrosis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 1/137 (0.7%) 1 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 7/90 (7.8%) 8 8/187 (4.3%) 8 4/180 (2.2%) 4 10/170 (5.9%) 10 6/242 (2.5%) 6 17/338 (5%) 17 1/70 (1.4%) 1 4/140 (2.9%) 4 4/137 (2.9%) 4 1/46 (2.2%) 1 3/95 (3.2%) 3 2/92 (2.2%) 2 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 1/6 (16.7%) 1 1/2 (50%) 1
    Respiratory failure 6/90 (6.7%) 8 15/187 (8%) 15 12/180 (6.7%) 12 15/170 (8.8%) 15 23/242 (9.5%) 24 22/338 (6.5%) 22 2/70 (2.9%) 2 5/140 (3.6%) 5 4/137 (2.9%) 5 2/46 (4.3%) 2 10/95 (10.5%) 10 7/92 (7.6%) 7 1/8 (12.5%) 1 1/12 (8.3%) 1 1/15 (6.7%) 1 1/15 (6.7%) 1 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Hypoxia 4/90 (4.4%) 7 3/187 (1.6%) 3 5/180 (2.8%) 5 4/170 (2.4%) 4 5/242 (2.1%) 5 11/338 (3.3%) 11 2/70 (2.9%) 2 0/140 (0%) 0 1/137 (0.7%) 1 2/46 (4.3%) 2 2/95 (2.1%) 2 1/92 (1.1%) 1 1/8 (12.5%) 1 1/12 (8.3%) 1 1/15 (6.7%) 1 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Acute respiratory distress syndrome 1/90 (1.1%) 1 3/187 (1.6%) 3 0/180 (0%) 0 2/170 (1.2%) 2 2/242 (0.8%) 2 4/338 (1.2%) 4 2/70 (2.9%) 2 2/140 (1.4%) 2 2/137 (1.5%) 2 0/46 (0%) 0 1/95 (1.1%) 1 2/92 (2.2%) 2 0/8 (0%) 0 0/12 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0 1/16 (6.3%) 1 0/6 (0%) 0 0/2 (0%) 0
    Hypercapnia 1/90 (1.1%) 1 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 2/95 (2.1%) 2 2/92 (2.2%) 2 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pneumothorax 1/90 (1.1%) 1 2/187 (1.1%) 2 2/180 (1.1%) 2 5/170 (2.9%) 5 8/242 (3.3%) 10 9/338 (2.7%) 12 1/70 (1.4%) 1 0/140 (0%) 0 1/137 (0.7%) 2 1/46 (2.2%) 1 2/95 (2.1%) 2 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 1/16 (6.3%) 1 0/6 (0%) 0 0/2 (0%) 0
    Pulmonary embolism 1/90 (1.1%) 2 4/187 (2.1%) 4 4/180 (2.2%) 4 1/170 (0.6%) 1 6/242 (2.5%) 6 4/338 (1.2%) 4 0/70 (0%) 0 4/140 (2.9%) 4 2/137 (1.5%) 2 0/46 (0%) 0 2/95 (2.1%) 2 2/92 (2.2%) 2 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pulmonary hypertension 1/90 (1.1%) 1 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Respiratory acidosis 1/90 (1.1%) 1 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 2/95 (2.1%) 2 2/92 (2.2%) 2 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Respiratory distress 1/90 (1.1%) 1 0/187 (0%) 0 1/180 (0.6%) 1 2/170 (1.2%) 2 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 1/92 (1.1%) 1 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Tachypnoea 1/90 (1.1%) 1 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 1/46 (2.2%) 1 0/95 (0%) 0 0/92 (0%) 0 1/8 (12.5%) 1 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Acquired diaphragmatic eventration 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Apnoea 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 2/95 (2.1%) 2 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Aspiration 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Asthma 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 1/137 (0.7%) 1 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Atelectasis 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Bronchial haemorrhage 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Bronchial obstruction 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Bronchial secretion retention 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Chronic obstructive pulmonary disease 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Chronic respiratory failure 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 2/95 (2.1%) 2 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Cystic lung disease 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Diffuse alveolar damage 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 1/137 (0.7%) 1 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Dyspnoea 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Haemothorax 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 1/242 (0.4%) 1 2/338 (0.6%) 2 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Lung infiltration 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 1/170 (0.6%) 1 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Non-cardiogenic pulmonary oedema 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pleural effusion 0/90 (0%) 0 0/187 (0%) 0 2/180 (1.1%) 2 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pneumomediastinum 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 3/170 (1.8%) 3 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pneumonia aspiration 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 2/137 (1.5%) 2 0/46 (0%) 0 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pneumothorax spontaneous 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 2 1/170 (0.6%) 1 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Respiratory arrest 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Respiratory tract oedema 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 1/242 (0.4%) 1 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Stridor 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Skin and subcutaneous tissue disorders
    Angioedema 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Decubitus ulcer 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Dermatitis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Dermatitis contact 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Livedo reticularis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Subcutaneous emphysema 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Vascular disorders
    Deep vein thrombosis 1/90 (1.1%) 1 4/187 (2.1%) 6 9/180 (5%) 11 4/170 (2.4%) 4 8/242 (3.3%) 8 12/338 (3.6%) 12 0/70 (0%) 0 0/140 (0%) 0 1/137 (0.7%) 1 1/46 (2.2%) 1 1/95 (1.1%) 1 2/92 (2.2%) 2 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 1/6 (16.7%) 1 0/2 (0%) 0
    Haemorrhage 1/90 (1.1%) 1 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Arterial thrombosis 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Distributive shock 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Dry gangrene 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Embolism 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 1/170 (0.6%) 1 1/242 (0.4%) 1 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Haematoma 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Hypertension 0/90 (0%) 0 1/187 (0.5%) 1 3/180 (1.7%) 3 0/170 (0%) 0 0/242 (0%) 0 2/338 (0.6%) 2 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 1/46 (2.2%) 1 2/95 (2.1%) 2 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 1/16 (6.3%) 1 0/6 (0%) 0 0/2 (0%) 0
    Hypotension 0/90 (0%) 0 4/187 (2.1%) 5 3/180 (1.7%) 3 6/170 (3.5%) 6 6/242 (2.5%) 7 10/338 (3%) 10 0/70 (0%) 0 0/140 (0%) 0 1/137 (0.7%) 1 0/46 (0%) 0 2/95 (2.1%) 2 5/92 (5.4%) 5 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Hypovolaemic shock 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Jugular vein thrombosis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 2/242 (0.8%) 2 1/338 (0.3%) 1 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 1/95 (1.1%) 1 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pelvic venous thrombosis 0/90 (0%) 0 1/187 (0.5%) 1 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Peripheral artery occlusion 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Peripheral ischaemia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 2/170 (1.2%) 2 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Shock 0/90 (0%) 0 2/187 (1.1%) 2 1/180 (0.6%) 1 2/170 (1.2%) 2 1/242 (0.4%) 1 5/338 (1.5%) 5 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 1/8 (12.5%) 1 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Shock haemorrhagic 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 1/12 (8.3%) 1 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Thrombosis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 1/140 (0.7%) 1 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Vena cava thrombosis 0/90 (0%) 0 0/187 (0%) 0 1/180 (0.6%) 1 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Other (Not Including Serious) Adverse Events
    Phase 2: Placebo Phase 2: Sarilumab 200mg IV Phase 2: Sarilumab 400mg IV Phase 3 Cohort 1: Placebo - Critical Phase 3 Cohort 1: Sarilumab 200mg IV - Critical Phase 3 Cohort 1: Sarilumab 400mg IV - Critical Phase 3 Cohort 1: Placebo - Severe Phase 3 Cohort 1: Sarilumab 200mg IV - Severe Phase 3 Cohort 1: Sarilumab 400mg IV - Severe Phase 3 Cohort 1: Placebo - MSOD Phase 3 Cohort 1: Sarilumab 200 mg IV - MSOD Phase 3 Cohort 1: Sarilumab 400 mg IV - MSOD Phase 3 Cohort 1: Placebo - Immunocompromised Phase 3 Cohort 1: Sarilumab 200 mg IV - Immunocompromised Phase 3 Cohort 1: Sarilumab 400 mg IV - Immunocompromised Phase 3 Cohort 2: Placebo Phase 3 Cohort 2: Sarilumab 800 mg IV Phase 3 Cohort 3: Placebo Phase 3 Cohort 3: Sarilumab 800 mg IV
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 20/90 (22.2%) 48/187 (25.7%) 44/180 (24.4%) 24/170 (14.1%) 57/242 (23.6%) 83/338 (24.6%) 0/70 (0%) 0/140 (0%) 8/137 (5.8%) 17/46 (37%) 23/95 (24.2%) 15/92 (16.3%) 3/8 (37.5%) 5/12 (41.7%) 6/15 (40%) 5/15 (33.3%) 7/16 (43.8%) 1/6 (16.7%) 2/2 (100%)
    Blood and lymphatic system disorders
    Neutropenia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0 1/16 (6.3%) 1 0/6 (0%) 0 0/2 (0%) 0
    Hepatobiliary disorders
    Cholangitis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 1/12 (8.3%) 1 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Infections and infestations
    Acinetobacter infection 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Bacteraemia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1 1/16 (6.3%) 1 0/6 (0%) 0 0/2 (0%) 0
    Clostridium difficile colitis 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 2/15 (13.3%) 2 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Enterobacter bacteraemia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Escherichia bacteraemia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Fungaemia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 2/15 (13.3%) 2 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Fungal infection 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 1/8 (12.5%) 1 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pneumonia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 5/95 (5.3%) 5 0/92 (0%) 0 0/8 (0%) 0 1/12 (8.3%) 1 1/15 (6.7%) 1 1/15 (6.7%) 1 1/16 (6.3%) 1 0/6 (0%) 0 0/2 (0%) 0
    Pneumonia escherichia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pneumonia klebsiella 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 1/15 (6.7%) 1 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Pseudomonas infection 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 1/8 (12.5%) 1 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Staphylococcal bacteraemia 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 1/12 (8.3%) 1 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 1/6 (16.7%) 1 0/2 (0%) 0
    Staphylococcal infection 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 3/46 (6.5%) 3 6/95 (6.3%) 6 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 1/16 (6.3%) 1 0/6 (0%) 0 1/2 (50%) 1
    Urinary tract infection 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 1/15 (6.7%) 1 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Investigations
    Aspartate aminotransferase increased 15/90 (16.7%) 18 30/187 (16%) 32 30/180 (16.7%) 31 16/170 (9.4%) 17 36/242 (14.9%) 38 36/338 (10.7%) 40 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 12/46 (26.1%) 15 12/95 (12.6%) 15 10/92 (10.9%) 13 1/8 (12.5%) 1 1/12 (8.3%) 1 2/15 (13.3%) 2 1/15 (6.7%) 1 2/16 (12.5%) 2 0/6 (0%) 0 0/2 (0%) 0
    Alanine aminotransferase increased 13/90 (14.4%) 15 38/187 (20.3%) 41 30/180 (16.7%) 32 19/170 (11.2%) 19 42/242 (17.4%) 46 51/338 (15.1%) 53 0/70 (0%) 0 0/140 (0%) 0 8/137 (5.8%) 8 9/46 (19.6%) 9 7/95 (7.4%) 7 11/92 (12%) 13 1/8 (12.5%) 1 1/12 (8.3%) 1 1/15 (6.7%) 1 1/15 (6.7%) 1 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Hepatic enzyme increased 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 1/16 (6.3%) 1 0/6 (0%) 0 0/2 (0%) 0
    Liver function test increased 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 3/46 (6.5%) 3 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 3/12 (25%) 3 0/15 (0%) 0 1/15 (6.7%) 1 1/16 (6.3%) 1 0/6 (0%) 0 0/2 (0%) 0
    Transaminases increased 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 24/338 (7.1%) 25 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 1/12 (8.3%) 1 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 1/2 (50%) 1
    Vascular disorders
    Hypotension 0/90 (0%) 0 0/187 (0%) 0 0/180 (0%) 0 0/170 (0%) 0 0/242 (0%) 0 0/338 (0%) 0 0/70 (0%) 0 0/140 (0%) 0 0/137 (0%) 0 0/46 (0%) 0 0/95 (0%) 0 0/92 (0%) 0 1/8 (12.5%) 1 0/12 (0%) 0 0/15 (0%) 0 0/15 (0%) 0 0/16 (0%) 0 0/6 (0%) 0 0/2 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The investigator has the right to independently publish study results from the investigator's site after a multi-center publication, or a defined period after the completion of the study by all sites. The investigator must provide the sponsor a copy of any such publication derived from the study for review and comment in advance of any submission, and delay publication, if requested, to allow the Sponsor to preserve its proprietary rights.

    Results Point of Contact

    Name/Title Clinical Trials Adminstrator
    Organization Regeneron Pharmaceuticals, Inc.
    Phone 844-734-6643
    Email clinicaltrials@regeneron.com
    Responsible Party:
    Regeneron Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT04315298
    Other Study ID Numbers:
    • 6R88-COV-2040
    First Posted:
    Mar 19, 2020
    Last Update Posted:
    Sep 23, 2021
    Last Verified:
    Sep 1, 2021