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An Adaptive Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study Assessing Efficacy and Safety of Sarilumab for Hospitalized Patients With COVID-19

Trial Profile

An Adaptive Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study Assessing Efficacy and Safety of Sarilumab for Hospitalized Patients With COVID-19

Status: Discontinued
Phase of Trial: Phase II/III

Latest Information Update: 27 Sep 2021

At a glance

  • Drugs Sarilumab (Primary)
  • Indications COVID 2019 infections; COVID-19 pneumonia; Hypoxaemia; Respiratory insufficiency
  • Focus Pharmacodynamics; Therapeutic Use
  • Sponsors Regeneron Pharmaceuticals
  • Most Recent Events

    • 23 Sep 2021 Biomarkers information updated
    • 08 Sep 2021 Results of this post-hoc analyses published in the Journal of Infectious Diseases
    • 16 Jul 2020 Planned End Date changed from 20 Jul 2021 to 31 Aug 2020.

Trial Overview

Outcome

Primary endpoint not met - negative

Purpose

This phase 2/3 study is investigating addition of Kevzara (sailumab) to usual supportive care, compared to supportive care plus placebo in patients with severe COVID-19 infection across approximately 16 U.S. sites.
This adaptive design study has two parts: first part will evaluate the impact of Kevzara on fever and patients' need for supplemental oxygen. The second, larger part of the trial will evaluate the improvement in longer-term outcomes including preventing death and reducing the need for mechanical ventilation, supplemental oxygen and/or hospitalization.

Comments

According to a Regeneron Pharmaceuticals Media Release, based on the latest results ( 400mg cohort), the trial did not meet its primary and key secondary endpoints. So, the company has been stopped this study.

Primary Endpoints

Not met, 02 Jul 2020

Proportion of patients with at least 1-point improvement in clinical status using the 7-point ordinal scale in patients with critical COVID-19 receiving mechanical ventilation at baseline

description: Phase 3 Cohort 1

7-point Ordinal Scale

Death;

Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO);

Hospitalized, requiring non-invasive ventilation or high flow oxygen devices;

Hospitalized, requiring supplemental oxygen;

Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise)

Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care

Not hospitalized

time_frame: Up to day 22 [1]

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

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

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

Other Endpoints

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

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

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

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

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

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

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

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

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

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

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

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

Percentage of Participants Alive, Off Oxygen (Phase 2)

time_frame: At Day 29

Number of Days of Resting Respiratory Rate >24 Breaths/Min (Phase 2)

time_frame: Up to day 29

Number of Days With Hypoxemia (Phase 2)

time_frame: Up to day 29

Number of Days of Supplemental Oxygen Use (Phase 2)

time_frame: Up to day 29

Time to Saturation ≥94% on Room Air (Phase 2)

time_frame: Up to day 29

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

Number of Participants Who Initiated Mechanical Ventilation After Baseline (Phase 2)

time_frame: Up to Day 29

Number of Days in an Intensive Care Unit (ICU) in Participants Who Were Not in ICU at Baseline (Phase 2)

time_frame: Up to Day 29

Number of Days of Hospitalization Among Survivors (Phase 2)

time_frame: Up to day 29

Number of Deaths Due to Any Cause

description: Number of deaths due to any cause (All-Cause Mortality)
time_frame: Up to day 60

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

time_frame: Day 22

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

time_frame: Day 22

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

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

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

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

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

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

Time to Death (Phase 3 Cohort 1: Critical ITT)

description: Time to Death (All-Cause Mortality)
time_frame: Up to day 60

Time to Death (Phase 3 Cohort 2)

description: Time to Death (All-Cause Mortality)
time_frame: Up to day 60

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

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

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

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

Number of Participants With Any Serious Adverse Event

time_frame: Up to day 60

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

Number of Participants With Severe or Life-threatening Bacterial, Invasive Fungal, or Opportunistic Infection

time_frame: Up to day 60

Number of Participants With Grade 4 Neutropenia and Concurrent Invasive Infection

time_frame: Up to day 60

Number of Participants With Grade ≥2 Infusion Related Reactions

time_frame: Up to day 60

Number of Participants With Grade ≥2 Hypersensitivity Reactions

time_frame: Up to day 60

Number of Participants With Gastrointestinal Perforation

time_frame: Up to day 60

Mean Observed Leukocyte Values Across Study Days (Phase 2)

time_frame: Days 1, 4, 15 and 29

Mean Observed Leukocyte Values Across Study Days (Phase 3)

time_frame: Days 1, 4, 15 and 29

Mean Observed Hemoglobin Values Across Study Days (Phase 2)

time_frame: Days 1, 4, 15 and 29

Mean Observed Hemoglobin Values Across Study Days (Phase 3)

time_frame: Days 1, 4, 15 and 29

Mean Observed Platelet Count Across Study Days (Phase 2)

time_frame: Days 1, 4, 15 and 29

Mean Observed Platelet Count Across Study Days (Phase 3)

time_frame: Days 1, 4, 15 and 29

Mean Observed Total Bilirubin Values Across Study Days (Phase 2)

time_frame: Days 1, 4, 15 and 29

Mean Observed Total Bilirubin Across Study Days (Phase 3)

time_frame: Days 1, 4, 15 and 29

Mean Observed Aspartate Aminotransferase Values Across Study Days (Phase 2)

time_frame: Days 1, 4, 15 and 29

Mean Observed Aspartate Aminotransferase Values Across Study Days (Phase 3)

time_frame: Days 1, 4, 15 and 29

Mean Observed Alanine Aminotransferase Values Across Study Days (Phase 2)

time_frame: Days 1, 4, 15 and 29

Mean Observed Alanine Aminotransferase Values Across Study Days (Phase 3)

time_frame: Days 1, 4, 15 and 29

Mean Observed Creatinine Values Across Study Days (Phase 2)

time_frame: Days 1, 4, 15 and 29

Mean Observed Creatinine Values Across Study Days (Phase 3)

time_frame: Days 1, 4, 15 and 29 [2]

Diseases Treated

Indication Qualifiers Patient Segments
COVID 2019 infections treatment -
COVID-19 pneumonia treatment -
Hypoxaemia treatment -
Respiratory insufficiency treatment -

Biomarker

NCT Number Biomarker Name Biomarker Function
NCT04315298 ALT Outcome Measure
C-reactive protein (CRP) Outcome Measure
Interleukin-6 (IL-6) Outcome Measure
L-Aspartic acid Outcome Measure
For more detail, check out BiomarkerBase: the leading source of information about biomarkers used in drug development and diagnostic tests, tracking a comprehensive list of biomarker uses worldwide by over 800 companies

Subjects

  • Subject Type patients
  • Number

    Planned: 2500

    Actual: 1912

  • Sex male & female
  • Age Group ≥ 18 years; adult

Patient Inclusion Criteria

Key - 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

Patient 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

Trial Details

Identifiers

Identifier Owner
NCT04315298 ClinicalTrials.gov: US National Institutes of Health
6R88COV2040 -

Organisations

  • Sponsors Regeneron Pharmaceuticals
  • Affiliations Regeneron Pharmaceuticals; Sanofi

Trial Dates

  • Initiation Dates

    Actual : 18 Mar 2020

  • Primary Completion Dates

    Planned : 24 Jul 2020

    Actual : 24 Jul 2020

  • End Dates

    Planned : 31 Aug 2020

    Actual : 02 Sep 2020

Other Details

  • Design double-blind; multicentre; parallel; prospective; randomised
  • Phase of Trial Phase II/III
  • Location USA
  • Focus Pharmacodynamics; Therapeutic Use

Interventions

Drugs Route Formulation
SarilumabPrimary Drug Intravenous Infusion

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 Name: Kevzara®, REGN88, SAR153191 Drug: Placebo (Single or multiple intravenous (IV) doses of placebo to match sarilumab administration)

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 Name: Kevzara®, REGN88, SAR153191 Drug: Placebo (Single or multiple intravenous (IV) doses of placebo to match sarilumab administration)

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 Name: Kevzara®, REGN88, SAR153191 Drug: Placebo (Single or multiple intravenous (IV) doses of placebo to match sarilumab administration)

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 Name: Kevzara®, REGN88, SAR153191 Drug: Placebo (Single or multiple intravenous (IV) doses of placebo to match sarilumab administration)

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 Name: Kevzara®, REGN88, SAR153191 Drug: Placebo (Single or multiple intravenous (IV) doses of placebo to match sarilumab administration)

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 Name: Kevzara®, REGN88, SAR153191 Drug: Placebo (Single or multiple intravenous (IV) doses of placebo to match sarilumab administration)

Results

Therapeutic efficacy

Updates results from the phase III portion of the trial showed that following treatment with sarilumab, minor positive trends were observed in the primary pre-specified analysis group (n = 194) (critical patients on sarilumab 400 mg who were mechanically ventilated at baseline) however statistical significance was not achieved. These were countered by negative trends in a subgroup of critical patients who were not mechanically ventilated at baseline including the proportion of patients with a 1-point improvement on day 22 (primary endpoint for mechanical ventilation group); the proportion of patients who died by day 29; and the proportion of patients who recovered by day 22. Preliminary results from the phase II portion of the phase II/III trial showed that primary end point of the trial was met as indicated by rapidly lowered C-reactive protein in sarilumab treated patients. Baseline levels of IL-6 were elevated across all treatment arms, with higher levels observed in "critical" patients compared to "severe" patients. Explorarory analysis results showed that no notable benefit on clinical outcomes when combining the "severe" and "critical" groups, versus placebo was observed in sarilumab treated patients. However, negative trends for most outcomes in the "severe" group, while positive trends for all outcomes in the "critical" group were observed. Review of the discontinued "severe" group data revealed that the negative trends in the phase II trial (n=126) were not reproduced in phase III trial (n=276), and that clinical outcomes were balanced across the sarilumab and placebo treatment arms. Outcomes for the "severe" group were better than expected based on prior reports, regardless of treatment assignment as evident from example that in the phase II portion, approximately 80% were discharged, 10% of patients died and 10% remain hospitalized in the severe group [1] [3] .
2020-07-06 14:23:00.990

Adverse events

COVID-2019 infections: Updated resultd from the phase III portion of the trial showed that in the primary analysis group (n = 194) adverse events were experienced by 80% of sarilumab patients and 77% of placebo patients. Multi-organ dysfunction syndrome (6% sarilumab, 5% placebo) and hypotension (4% sarilumab, 3% placebo) were the serious adverse events reported in at least 3% of patients and more frequently among sarilumab patients [1] [3] .

Publications

  1. Regeneron Pharmaceuticals. Regeneron and Sanofi Provide Update on Kevzara(RM) (sarilumab) Phase 3 U.S. Trial in COVID-19 Patients. Media-Rel 2020;.

    Media Release
  2. Regeneron Pharmaceuticals, Sanofi. Regeneron and Sanofi Provide Update on U.S. Phase 2/3 Adaptive-Designed Trial of Kevzara(Rm) (sarilumab) in Hospitalized COVID-19 Patients. Media-Rel 2020;.

    Media Release
  3. Boyapati A, Wipperman MF, Ehmann PJ, Hamon S, Lederer DJ, Waldron A, et al. Baseline SARS-CoV-2 Viral Load is Associated With COVID-19 Disease Severity and Clinical Outcomes: Post-Hoc Analyses of a Phase 2/3 Trial. . J-Infect-Dis 2021;.

    PubMed | CrossRef Fulltext
  4. Sanofi. Sanofi and Regeneron provide update on U.S. Phase 2/3 adaptive-designed trial in hospitalized COVID-19 patients. Media-Rel 2020;.

    Media Release
  5. Sanofi. Sanofi and Regeneron provide update on Kevzara(Rm) (sarilumab) Phase 3 U.S. trial in COVID-19 patients. Media-Rel 2020;.

    Media Release

Authors

Author Total Publications First Author Last Author
Bhore R 1 - -
Boyapati A 1 1 -
Ehmann PJ 1 - -
Flanagan JJ 1 - -
Hamilton JD 1 - -
Hamon S 1 - -
Karayusuf E 1 - -
Lederer DJ 1 - -
Nivens MC 1 - -
Regeneron Pharmaceuticals 2 2 1
Sanofi 3 2 3
Sivapalasingam S 1 - 1
Sumner G 1 - -
Waldron A 1 - -
Wipperman MF 1 - -

Trial Centres

Centres

Centre Name Location Trial Centre Country
Regeneron Pharmaceuticals
Clinical Trials Administrator
844-734-6643
clinicaltrials@regeneron.com
show details
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Regeneron Study Site Ann Arbor, Michigan USA
Regeneron Study Site Atlanta, Georgia USA
Regeneron Study Site Aurora, Colorado USA
Regeneron Study Site Boston, Massachusetts USA
Regeneron Study Site Bronx, New York USA
Regeneron Study Site Brooklyn, New York USA
Regeneron Study Site Buffalo, New York USA
Regeneron Study Site Chicago, Illinois USA
Regeneron Study Site Dallas, Texas USA
Regeneron Study Site Danville, Pennsylvania USA
Regeneron Study Site Decatur, Georgia USA
Regeneron Study Site Denver, Colorado USA
Regeneron Study Site Edison, New Jersey USA
Regeneron Study Site Elmhurst, New York USA
Regeneron Study Site Everett, Washington USA
Regeneron Study Site Falls Church, Virginia USA
Regeneron Study Site Gainesville, Florida USA
Regeneron Study Site Hackensack, New Jersey USA
Regeneron Study Site Livingston, New Jersey USA
Regeneron Study Site Los Angeles, California USA
Regeneron Study Site Marietta, Georgia USA
Regeneron Study Site Morristown, New Jersey USA
Regeneron Study Site Murray, Utah USA
Regeneron Study Site Neptune, New Jersey USA
Regeneron Study Site New Haven, Connecticut USA
Regeneron Study Site New Orleans, Louisiana USA
Regeneron Study Site New York, New York USA
Regeneron Study Site Newark, New Jersey USA
Regeneron Study Site Orlando, Florida USA
Regeneron Study Site Philadelphia, Pennsylvania USA
Regeneron Study Site Portland, Oregon USA
Regeneron Study Site Renton, Washington USA
Regeneron Study Site Richmond, Virginia USA
Regeneron Study Site Rochester, Minnesota USA
Regeneron Study Site Sacramento, California USA
Regeneron Study Site Santa Monica, California USA
Regeneron Study Site Scranton, Pennsylvania USA
Regeneron Study Site Stony Brook, New York USA
Regeneron Study Site Tampa, Florida USA
Regeneron Study Site Teaneck, New Jersey USA
Regeneron Study Site Tulsa, Oklahoma USA
Regeneron Study Site Valhalla, New York USA
Regeneron Study Site Washington, District of Columbia USA
Regeneron Study Site Wilkes-Barre, Pennsylvania USA
Regeneron Study Site 1 Bronx, New York USA
Regeneron Study Site 1 Manhasset, New York USA
Regeneron Study Site 1 New York, New York USA
Regeneron Study Site 2 Bronx, New York USA
Regeneron Study Site 2 Manhasset, New York USA
Regeneron Study Site 2 New York, New York USA
Sanofi
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Trial History

Event Date Event Type Comment
27 Sep 2021 Other trial event Last checked against Clinicaltrials.gov record. Updated 27 Sep 2021
23 Sep 2021 Biomarker Update Biomarkers information updated Updated 25 Sep 2021
08 Sep 2021 Results Results of this post-hoc analyses published in the Journal of Infectious Diseases Updated 15 Sep 2021
16 Jul 2020 Completion date Planned End Date changed from 20 Jul 2021 to 31 Aug 2020. Updated 22 Jul 2020
16 Jul 2020 Other trial event Planned primary completion date changed from 20 May 2021 to 24 Jul 2020. Updated 22 Jul 2020
02 Jul 2020 Results Results (n=194) presented in a Sanofi Media Release. Updated 09 Jul 2020
02 Jul 2020 Endpoint not met Primary endpoint did not met (Proportion of patients with at least 1-point improvement in clinical status using the 7-point ordinal scale in patients with critical COVID-19 receiving mechanical ventilation at baseline), according to a Regeneron Pharmaceuticals media release. Updated 07 Jul 2020
02 Jul 2020 Other trial event According to a Regeneron Pharmaceuticals Media Release, 21 patients are enrolled in the second cohort (800 mg). However, the company now has stopped the study. Updated 07 Jul 2020
02 Jul 2020 Other trial event According to a Regeneron Pharmaceuticals Media Release, data from this study will be submitted to a peer-reviewed publication later this year. Updated 07 Jul 2020
02 Jul 2020 Other trial event According to a Regeneron Pharmaceuticals Media Release, based on the latest results ( 400mg cohort), the trial did not meet its primary and key secondary endpoints. So, the company has been stopped this study. Updated 07 Jul 2020
02 Jul 2020 Status change - discontinued Status changed from recruiting to discontinued, according to a Regeneron Pharmaceuticals Media Release. Updated 07 Jul 2020
02 Jul 2020 Results Results (n=194) presented in a Regeneron Pharmaceuticals media release. Updated 07 Jul 2020
04 Jun 2020 Other trial event Planned number of patients changed from 400 to 2500. Updated 10 Jun 2020
04 Jun 2020 Completion date Planned End Date changed from 1 Apr 2021 to 20 Jul 2021. Updated 10 Jun 2020
04 Jun 2020 Other trial event Planned primary completion date changed from 9 Mar 2021 to 20 May 2021. Updated 10 Jun 2020
27 Apr 2020 Results Results presented in a Sanofi Media Release. Updated 30 Apr 2020
27 Apr 2020 Other trial event According to a Regeneron Pharmaceuticals Media Release, this trial has been funded in part with Federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; and BARDA, under OT number: HHSO100201700020C. Updated 29 Apr 2020
27 Apr 2020 Other trial event According to a Regeneron Pharmaceuticals Media Release, enrollment in the phase 3 portion is ongoing currently includes more than 600 patients in the "critical" group. Regeneron and Sanofi remain blinded to the ongoing portion of the Phase 3 trial and expect to report results by June. Updated 29 Apr 2020
27 Apr 2020 Protocol amendment According to a Regeneron Pharmaceuticals Media Release, Independent Data Monitoring Committee recommended continuing ongoing Phase 3 trial only in the more advanced "critical" group with Kevzara higher-dose (400mg) versus placebo and to discontinue lower-dose Kevzara (200 mg). Updated 29 Apr 2020
27 Apr 2020 Results Results presented in the Regeneron Pharmaceuticals Media Release. Updated 29 Apr 2020
02 Apr 2020 Completion date Planned End Date changed from 16 Mar 2021 to 1 Apr 2021. Updated 07 Apr 2020
02 Apr 2020 Other trial event Planned primary completion date changed from 16 Mar 2021 to 9 Mar 2021. Updated 07 Apr 2020
21 Mar 2020 Other trial event According to a US Department of Health and Human Services media release, the company will receive funds from the U.S. Department of Health and Human Services' Office of the Assistant Secretary for Preparedness and Response (ASPR) for this trial. Updated 26 Mar 2020
20 Mar 2020 Other trial event According to the Feinstein Institute for Medical Research media release, the lead investigator on this study is Negin Hajizadeh, MD, assistant professor in the Institute of Health Innovations & Outcomes Research at Feinstein, and a pulmonary and critical care physician. Updated 23 Mar 2020
20 Mar 2020 Other trial event New source identified and integrated (ClinicalTrials.gov: NCT04315298). Updated 20 Mar 2020
18 Mar 2020 New trial record New trial record Updated 18 Mar 2020
16 Mar 2020 Other trial event According to a Regeneron Pharmaceuticals media release, Regeneron Pharmaceuticals and Sanofi have started a clinical program evaluating Kevzara (sarilumab) in patients hospitalized with severe COVID-19 infection.Regeneron is leading this U.S. trial, Sanofi will lead upcoming ex-U.S. trials. Updated 20 Mar 2020
16 Mar 2020 Other trial event According to a Regeneron Pharmaceuticals media release, if the trial continues with all three treatment arms to the end, it is expected to enroll approximately 400 patients, depending on the status of the COVID-19 outbreak and the proportion of patients with severe COVID-19 and high levels of IL-6. Updated 20 Mar 2020
16 Mar 2020 Other trial event According to a Regeneron Pharmaceuticals media release, Regeneron and Sanofi have worked closely with the U.S. Food and Drug Administration and the Biomedical Advanced Research and Development Authority, to initiate this trial quickly, so that the results may inform evidence-based treatment of this ongoing pandemic of COVID-19.Regeneron is leading U.S. trials, Sanofi will lead upcoming ex-U.S. trials. Updated 20 Mar 2020
16 Mar 2020 Other trial event According to a Regeneron Pharmaceuticals media release, the Phase 2 findings will be utilized in an adaptive manner to determine transition into Phase 3, helping to determine the endpoints, patient numbers and doses.The second, larger part of the trial will evaluate the improvement in longer-term outcomes including preventing death and reducing the need for mechanical ventilation, supplemental oxygen and/or hospitalization. Updated 20 Mar 2020
16 Mar 2020 Other trial event According to a Sanofi media release, this trial will begin at medical centers in New York, one of the epicenters of the U.S. COVID-19 outbreak. Updated 18 Mar 2020

References

  1. Regeneron Pharmaceuticals. Regeneron and Sanofi Provide Update on Kevzara(RM) (sarilumab) Phase 3 U.S. Trial in COVID-19 Patients. Media-Rel 2020;.

    Media Release
  2. ClinicalTrials.gov: US National Institutes of Health. Trial-Reg 2021;.

    Available from: URL: http://clinicaltrials.gov
  3. Regeneron Pharmaceuticals, Sanofi. Regeneron and Sanofi Provide Update on U.S. Phase 2/3 Adaptive-Designed Trial of Kevzara(Rm) (sarilumab) in Hospitalized COVID-19 Patients. Media-Rel 2020;.

    Media Release
  4. US Department of Health and Human Services. HHS Funds Phase 2/3 Clinical Trial for Potential Treatment for COVID-19. Media-Rel 2020;.

    Media Release
  5. Boyapati A, Wipperman MF, Ehmann PJ, Hamon S, Lederer DJ, Waldron A, et al. Baseline SARS-CoV-2 Viral Load is Associated With COVID-19 Disease Severity and Clinical Outcomes: Post-Hoc Analyses of a Phase 2/3 Trial. . J-Infect-Dis 2021;.

    PubMed | CrossRef Fulltext
  6. Sanofi. Sanofi and Regeneron begin global Kevzara(Rm) (sarilumab) clinical trial program in patients with severe COVID-19. Media-Rel 2020;.

    Media Release
  7. The Feinstein Institute for Medical Research. Feinstein Institutes begins enrolling patients in multiple COVID-19 clinical trials. Media-Rel 2020;.

    Media Release
  8. Sanofi. Sanofi and Regeneron provide update on U.S. Phase 2/3 adaptive-designed trial in hospitalized COVID-19 patients. Media-Rel 2020;.

    Media Release
  9. Regeneron Pharmaceuticals, Sanofi. Regeneron and Sanofi Begin Global Kevzara(R) (sarilumab) Clinical Trial Program in Patients with Severe COVID-19. Media-Rel 2020;.

    Media Release
  10. Sanofi. Sanofi and Regeneron provide update on Kevzara(Rm) (sarilumab) Phase 3 U.S. trial in COVID-19 patients. Media-Rel 2020;.

    Media Release
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