Clinical trial NCT04315298: Evaluation of the Efficacy and Safety of Sarilumab in Hospitalized Patients With COVID-19
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: COVID-19
Keywords: COVID-19
SARS-COV-2
coronavirus
IL-6
sarilumab
acute respiratory distress syndrome
treatment
Lead sponsor: Regeneron Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: Sanofi
First posted: 2020-03-19
Enrollment: 1912
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Eligibility criteria: 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

Primary outcomes:
measure: Percent Change From Baseline in CRP Levels at Day 4 in Participants With Serum IL-6 Level Greater Than the ULN (Phase 2)
timeFrame: Baseline and Day 4
measure: 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)
timeFrame: Day 22
measure: 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)
timeFrame: Day 22
Secondary outcomes:
measure: 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)
timeFrame: Up to Day 29
measure: Time to Improvement (2 Points) in Clinical Status Assessment in Severe or Critical Patients With All Serum IL-6 Levels (Phase 2)
timeFrame: Up to Day 29
measure: 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)
timeFrame: Up to Day 29
measure: Time to Resolution of Fever for at Least 48 Hours Without Antipyretics by Clinical Severity (Phase 2)
timeFrame: Up to day 29
measure: 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)
timeFrame: Up to Day 29
measure: Time to Improvement in Oxygenation for at Least 48 Hours (Phase 2)
timeFrame: Up to day 29
measure: Time to Improvement in Oxygenation for at Least 48 Hours by Baseline IL-6 Levels (Phase 2)
timeFrame: Up to day 29
measure: Time to Resolution of Fever and Improvement in Oxygenation for at Least 48 Hours (Phase 2)
timeFrame: Up to day 29
measure: Percentage of Participants in Each Clinical Status Category Using the 7-point Ordinal Scale up to Day 29 (Phase 2)
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Time to Discharge or to a National Early Warning Score 2 (NEWS2) of ≤2 and Maintained for 24 Hours (Phase 2)
timeFrame: Up to day 29
measure: Change From Baseline in NEWS2 Scoring System (Phase 2)
timeFrame: Days 3, 5, 8, 11, 15 and 29
measure: Number of Days With Fever (Phase 2)
timeFrame: Up to Day 29
measure: Percentage of Participants Alive, Off Oxygen (Phase 2)
timeFrame: At Day 29
measure: Number of Days of Resting Respiratory Rate >24 Breaths/Min (Phase 2)
timeFrame: Up to day 29
measure: Number of Days With Hypoxemia (Phase 2)
timeFrame: Up to day 29
measure: Number of Days of Supplemental Oxygen Use (Phase 2)
timeFrame: Up to day 29
measure: Time to Saturation ≥94% on Room Air (Phase 2)
timeFrame: Up to day 29
measure: Number of Ventilator Free Days (Phase 2)
timeFrame: Up to Day 22
measure: Number of Participants Who Initiated Mechanical Ventilation After Baseline (Phase 2)
timeFrame: Up to Day 29
measure: Number of Days in an Intensive Care Unit (ICU) in Participants Who Were Not in ICU at Baseline (Phase 2)
timeFrame: Up to Day 29
measure: Number of Days of Hospitalization Among Survivors (Phase 2)
timeFrame: Up to day 29
measure: Number of Deaths Due to Any Cause
timeFrame: Up to day 60
measure: 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)
timeFrame: Day 22
measure: Percentage of Participants Who Recover (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)
timeFrame: Day 22
measure: Percentage of Participants Who Recover (Phase 3 Cohort 1: Critical ITT)
timeFrame: Day 22
measure: Percentage of Participants Who Die (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)
timeFrame: Up to Day 29 and Day 60
measure: Percentage of Participants Who Die (Phase 3 Cohort 1: Critical ITT)
timeFrame: Up to Day 29 and Day 60
measure: Percentage of Participants Alive Not Receiving Mechanical Ventilation or ECMO at Day 22 (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)
timeFrame: At Day 22
measure: 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)
timeFrame: At Day 22
measure: Percentage of Participants Alive Not Receiving Mechanical Ventilation or ECMO at Day 22 (Phase 3 Cohort 1: Critical ITT)
timeFrame: At Day 22
measure: 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)
timeFrame: At Day 22
measure: 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)
timeFrame: Up to day 29
measure: Time to at Least 1-point Improvement in Clinical Status Assessment on the 7-point Ordinal Scale (Phase 3 Cohort 1: Critical ITT)
timeFrame: Up to day 29
measure: Time to at Least 1-point Improvement in Clinical Status Assessment on the 7-point Ordinal Scale (Phase 3 Cohort 2)
timeFrame: Up to day 29
measure: Time to at Least 2-point Improvement in Clinical Status Assessment on the 7-point Ordinal Scale (Phase 3 Cohort 1)
timeFrame: Up to day 29
measure: Time to at Least 2-point Improvement in Clinical Status Assessment on the 7-point Ordinal Scale (Phase 3 Cohort 1: Critical ITT)
timeFrame: Up to day 29
measure: Percentage of Participants Receiving Mechanical Ventilation or ECMO at Day 22 (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)
timeFrame: Day 22
measure: Percentage of Participants Receiving Mechanical Ventilation or ECMO at Day 22 (Phase 3 Cohort 1: Critical ITT)
timeFrame: Day 22
measure: Percentage of Patients Discharged and Alive (Phase 3 Cohort 1)
timeFrame: At Day 22
measure: Percentage of Participants Discharged and Alive at Day 22 (Phase 3 Cohort 1: Critical ITT)
timeFrame: At Day 22
measure: Time to Recovery (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)
timeFrame: Up to day 29
measure: Time to Recovery (Phase 3 Cohort 1: Critical ITT)
timeFrame: Up to day 29
measure: Time to Recovery (Phase 3 Cohort 2)
timeFrame: Up to day 29
measure: Time to Death (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)
timeFrame: Up to day 60
measure: Time to Death (Phase 3 Cohort 1: Critical ITT)
timeFrame: Up to day 60
measure: Time to Death (Phase 3 Cohort 2)
timeFrame: Up to day 60
measure: Number of Ventilator-Free Days (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)
timeFrame: Days 8, 15, 22 and 29
measure: Number of Ventilator-Free Days (Phase 3 Cohort 1: Critical ITT)
timeFrame: Days 8, 15, 22 and 29
measure: Number of Days of Hospitalization Among Survivors (Phase 3 Cohort 1)
timeFrame: Days 8, 15, 22 and 29
measure: Number of Days of Hospitalization Among Survivors (Phase 3 Cohort 1: Critical ITT)
timeFrame: Days 8, 15, 22 and 29
measure: Number of Participants With Any Serious Adverse Event
timeFrame: Up to day 60
measure: Number of Participants With Grade 4 Neutropenia (ANC <500/mm3)
timeFrame: Up to day 60
measure: Number of Participants With Severe or Life-threatening Bacterial, Invasive Fungal, or Opportunistic Infection
timeFrame: Up to day 60
measure: Number of Participants With Grade 4 Neutropenia and Concurrent Invasive Infection
timeFrame: Up to day 60
measure: Number of Participants With Grade >=2 Infusion Related Reactions
timeFrame: Up to day 60
measure: Number of Participants With Grade >=2 Hypersensitivity Reactions
timeFrame: Up to day 60
measure: Number of Participants With Gastrointestinal Perforation
timeFrame: Up to day 60
measure: Mean Observed Leukocyte Values Across Study Days (Phase 2)
timeFrame: Days 1, 4, 15 and 29
measure: Mean Observed Leukocyte Values Across Study Days (Phase 3)
timeFrame: Days 1, 4, 15 and 29
measure: Mean Observed Hemoglobin Values Across Study Days (Phase 2)
timeFrame: Days 1, 4, 15 and 29
measure: Mean Observed Hemoglobin Values Across Study Days (Phase 3)
timeFrame: Days 1, 4, 15 and 29
measure: Mean Observed Platelet Count Across Study Days (Phase 2)
timeFrame: Days 1, 4, 15 and 29
measure: Mean Observed Platelet Count Across Study Days (Phase 3)
timeFrame: Days 1, 4, 15 and 29
measure: Mean Observed Total Bilirubin Values Across Study Days (Phase 2)
timeFrame: Days 1, 4, 15 and 29
measure: Mean Observed Total Bilirubin Across Study Days (Phase 3)
timeFrame: Days 1, 4, 15 and 29
measure: Mean Observed Aspartate Aminotransferase Values Across Study Days (Phase 2)
timeFrame: Days 1, 4, 15 and 29
measure: Mean Observed Aspartate Aminotransferase Values Across Study Days (Phase 3)
timeFrame: Days 1, 4, 15 and 29
measure: Mean Observed Alanine Aminotransferase Values Across Study Days (Phase 2)
timeFrame: Days 1, 4, 15 and 29
measure: Mean Observed Alanine Aminotransferase Values Across Study Days (Phase 3)
timeFrame: Days 1, 4, 15 and 29
measure: Mean Observed Creatinine Values Across Study Days (Phase 2)
timeFrame: Days 1, 4, 15 and 29
measure: Mean Observed Creatinine Values Across Study Days (Phase 3)
timeFrame: Days 1, 4, 15 and 29
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Regeneron Study Site
state: California
city: Sacramento
country: United States
facility: Regeneron Study Site
state: California
city: Santa Monica
country: United States
facility: Regeneron Study Site
state: California
city: Aurora
country: United States
facility: Regeneron Study Site
state: Colorado
city: Denver
country: United States
facility: Regeneron Study Site
state: Colorado
city: New Haven
country: United States
facility: Regeneron Study Site
state: Connecticut
city: Washington
country: United States
facility: Regeneron Study Site
state: District of Columbia
city: Gainesville
country: United States
facility: Regeneron Study Site
state: Florida
city: Orlando
country: United States
facility: Regeneron Study Site
state: Florida
city: Tampa
country: United States
facility: Regeneron Study Site
state: Florida
city: Atlanta
country: United States
facility: Regeneron Study Site
state: Georgia
city: Decatur
country: United States
facility: Regeneron Study Site
state: Georgia
city: Marietta
country: United States
facility: Regeneron Study Site
state: Georgia
city: Chicago
country: United States
facility: Regeneron Study Site
state: Illinois
city: Chicago
country: United States
facility: Regeneron Study Site
state: Illinois
city: New Orleans
country: United States
facility: Regeneron Study Site
state: Louisiana
city: Boston
country: United States
facility: Regeneron Study Site
state: Massachusetts
city: Boston
country: United States
facility: Regeneron Study Site
state: Massachusetts
city: Boston
country: United States
facility: Regeneron Study Site
state: Massachusetts
city: Ann Arbor
country: United States
facility: Regeneron Study Site
state: Michigan
city: Rochester
country: United States
facility: Regeneron Study Site
state: Minnesota
city: Edison
country: United States
facility: Regeneron Study Site
state: New Jersey
city: Hackensack
country: United States
facility: Regeneron Study Site
state: New Jersey
city: Livingston
country: United States
facility: Regeneron Study Site
state: New Jersey
city: Morristown
country: United States
facility: Regeneron Study Site
state: New Jersey
city: Neptune
country: United States
facility: Regeneron Study Site
state: New Jersey
city: Newark
country: United States
facility: Regeneron Study Site
state: New Jersey
city: Teaneck
country: United States
facility: Regeneron Study Site
state: New Jersey
city: Bronx
country: United States
facility: Regeneron Study Site
state: New York
city: Bronx
country: United States
facility: Regeneron Study Site 1
state: New York
city: Bronx
country: United States
facility: Regeneron Study Site 2
state: New York
city: Bronx
country: United States
facility: Regeneron Study Site
state: New York
city: Brooklyn
country: United States
facility: Regeneron Study Site
state: New York
city: Buffalo
country: United States
facility: Regeneron Study Site
state: New York
city: Elmhurst
country: United States
facility: Regeneron Study Site
state: New York
city: Manhasset
country: United States
facility: Regeneron Study Site 1
state: New York
city: Manhasset
country: United States
facility: Regeneron Study Site 2
state: New York
city: New York
country: United States
facility: Regeneron Study Site
state: New York
city: New York
country: United States
facility: Regeneron Study Site
state: New York
city: New York
country: United States
facility: Regeneron Study Site 1
state: New York
city: New York
country: United States
facility: Regeneron Study Site 2
state: New York
city: New York
country: United States
facility: Regeneron Study Site
state: New York
city: New York
country: United States
facility: Regeneron Study Site
state: New York
city: New York
country: United States
facility: Regeneron Study Site
state: New York
city: New York
country: United States
facility: Regeneron Study Site
state: New York
city: New York
country: United States
facility: Regeneron Study Site
state: New York
city: Stony Brook
country: United States
facility: Regeneron Study Site
state: New York
city: Valhalla
country: United States
facility: Regeneron Study Site
state: New York
city: Tulsa
country: United States
facility: Regeneron Study Site
state: Oklahoma
city: Portland
country: United States
facility: Regeneron Study Site
state: Oregon
city: Portland
country: United States
facility: Regeneron Study Site
state: Oregon
city: Danville
country: United States
facility: Regeneron Study Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: Regeneron Study Site
state: Pennsylvania
city: Scranton
country: United States
facility: Regeneron Study Site
state: Pennsylvania
city: Wilkes-Barre
country: United States
facility: Regeneron Study Site
state: Pennsylvania
city: Dallas
country: United States
facility: Regeneron Study Site
state: Texas
city: Dallas
country: United States
facility: Regeneron Study Site
state: Texas
city: Murray
country: United States
facility: Regeneron Study Site
state: Utah
city: Falls Church
country: United States
facility: Regeneron Study Site
state: Virginia
city: Richmond
country: United States
facility: Regeneron Study Site
state: Virginia
city: Everett
country: United States
facility: Regeneron Study Site
state: Washington
city: Renton
country: United States
facility: Regeneron Study Site
state: Washington
Study officials:
affiliation: Regeneron Pharmaceuticals
name: Clinical Trial Management
role: STUDY_DIRECTOR
References:
citation: Sivapalasingam S, Lederer DJ, Bhore R, Hajizadeh N, Criner G, Hosain R, Mahmood A, Giannelou A, Somersan-Karakaya S, O'Brien MP, Boyapati A, Parrino J, Musser BJ, Labriola-Tompkins E, Ramesh D, Purcell LA, Gulabani D, Kampman W, Waldron A, Ng Gong M, Saggar S, Sperber SJ, Menon V, Stein DK, Sobieszczyk ME, Park W, Aberg JA, Brown SM, Kosmicki JA, Horowitz JE, Ferreira MA, Baras A, Kowal B, Thomas DiCioccio A, Akinlade B, Nivens MC, Braunstein N, Herman GA, Yancopoulos GD, Weinreich DM. Efficacy and Safety of Sarilumab in Hospitalized Patients With Coronavirus Disease 2019: A Randomized Clinical Trial. Clin Infect Dis. 2022 Aug 24;75(1):e380-e388. doi: 10.1093/cid/ciac153.
citation: Boyapati A, Wipperman MF, Ehmann PJ, Hamon S, Lederer DJ, Waldron A, Flanagan JJ, Karayusuf E, Bhore R, Nivens MC, Hamilton JD, Sumner G, Sivapalasingam S. Baseline Severe Acute Respiratory Syndrome Viral Load Is Associated With Coronavirus Disease 2019 Severity and Clinical Outcomes: Post Hoc Analyses of a Phase 2/3 Trial. J Infect Dis. 2021 Dec 1;224(11):1830-1838. doi: 10.1093/infdis/jiab445.