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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: Recruiting
Phase of Trial: Phase II/III

Latest Information Update: 27 Apr 2020

At a glance

  • Drugs Sarilumab (Primary)
  • Indications COVID 2019 infections
  • Focus Pharmacodynamics; Therapeutic Use
  • Sponsors Regeneron Pharmaceuticals
  • Most Recent Events

    • 27 Apr 2020 Results presented in a Sanofi Media Release.
    • 27 Apr 2020 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.
    • 27 Apr 2020 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.

Trial Overview

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.

Primary Endpoints

Phase 2 part of the trial: Reduction of fever

Time to resolution of fever for at least 48 hours without antipyretics for 48 hours

description: Phase 2
Defined as ≤36.6°C (axilla), ≤37.2°C (oral) or ≤37.8°C (rectal or tympanic)
time_frame: Up to day 29

Percentage of patients reporting each severity rating on a 6-point ordinal scale

description: Phase 3
6-point Ordinal Scale:
Death
Hospitalized, on invasive mechanical ventilation or ECMO;
Hospitalized, on non-invasive ventilation or high flow oxygen devices;
Hospitalized, requiring supplemental oxygen
Hospitalized, not requiring supplemental oxygen
Not hospitalized
time_frame: Day 15

Percent change in C-reactive protein (CRP) levels

description: Phase 2 Only
time_frame: Day 4

Time to improvement (2 points) in clinical status assessment using the 7-point ordinal scale in patients with serum IL-6 levels greater than the upper limit of normal

description: Phase 3 Only
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 29

Other Endpoints

Time to improvement (2 points) in clinical status assessment on the 7-point ordinal scale in severe or critical patients with serum IL-6 levels greater than the upper limit of normal

description: Phase 2 Only
time_frame: Up to day 29

Time to improvement (2 points) in clinical status assessment on the 7-point ordinal scale reporting in severe or critical patients with all IL-6 levels

description: Phase 2 Only
time_frame: Up to day 29

Time to resolution of fever for at least 48 hours without antipyretics in patients with documented fever

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)
Documented fever defined as ≥38°C (oral), ≥38.4°C (rectal or tympanic), or ≥37.6°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

description: 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 baseline IL-6 levels

description: 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 improvement in oxygenation for at least 48 hours

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 clinical severity

description: 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

description: 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

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

Mean change in the 7-point ordinal scale

time_frame: Up to day 29

Percentage of patients in each clinical status category using the 7-point ordinal scale

time_frame: Up to day 29

Time to discharge or to a National Early Warning Score 2 (NEWS2) of ≤2 and maintained for 24 hours

description: NEWS2 consists of: Physiological Parameters: Respiration rate (per minute), SpO2 Scale 1 (%), SpO2 Scale 2 (%), Use of Air or oxygen, Systolic blood pressure (mmHg), Pulse (per minute), Consciousness, Temperature (°C)
time_frame: Up to day 29

Change from baseline in NEWS2 scoring system

time_frame: Up to day 29

Number of days with fever

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

Proportion of patients alive, off oxygen

time_frame: Day 29

Number of days of resting respiratory rate >24 breaths/min

time_frame: Up to day 29

Number of days with hypoxemia

time_frame: Up to day 29

Number of days of supplemental oxygen use

time_frame: Up to day 29

Time to saturation ≥94% on room air

time_frame: Up to day 29

Number of ventilator free days in the first 28 days

time_frame: Baseline to day 29

Number of patients requiring initiation of mechanical ventilation

time_frame: Up to day 29

Number of patients requiring non-invasive ventilation

time_frame: Up to day 29

Number of patients requiring the use of high flow nasal cannula

time_frame: Up to day 29

Number of patients admitted into an intensive care unit (ICU)

time_frame: Up to day 29

Number of days of hospitalization among survivors

time_frame: Up to day 29

Number of deaths due to any cause

time_frame: Up to day 60

Change in serum CRP levels

description: Phase 3 Only
time_frame: Up to day 29

Incidence of serious adverse events

time_frame: Up to Day 29

Incidence of Grade 4 neutropenia (ANC <500/mm3)

time_frame: Up to day 29

Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection

time_frame: Up to day 29

Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection in patients with Grade 4 neutropenia

time_frame: Up to day 29

Incidence of hypersensitivity reactions

time_frame: Up to day 29

Incidence of infusion reactions

time_frame: Up to day 29

Incidence of gastrointestinal perforation

time_frame: Up to day 29

White blood cell count

time_frame: Up to day 29 if still hospitalized

Hemoglobin levels

time_frame: Up to day 29 if still hospitalized

Platelet count

time_frame: Up to day 29 if still hospitalized

Creatinine levels

time_frame: Up to day 29 if still hospitalized

Total bilirubin level

time_frame: Up to day 29 if still hospitalized

Alanine aminotransferase (ALT) level

time_frame: Up to day 29 if still hospitalized

Aspartate aminotransferase (AST) level

time_frame: Up to day 29 if still hospitalized [1]

Diseases Treated

Indication Qualifiers Patient Segments
COVID 2019 infections treatment -

Subjects

  • Subject Type patients
  • Number

    Planned: 400

  • 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 and severe disease, critical disease, multi-system organ dysfunction or immunocompromised at baseline - 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) greater than 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 - Patients who have received immunosuppressive antibody therapy within the past 5 months, including intravenous immunoglobulin or plans to receive during the study period - 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 or compassionate use protocol 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 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 : 09 Mar 2021

  • End Dates

    Planned : 01 Apr 2021

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 Injection

Sarilumab high dose

Drug: Sarilumab (Single intravenous (IV) dose of sarilumab) Other Name: Kevzara®, REGN88, SAR153191

Sarilumab low dose

Drug: Sarilumab (Single intravenous (IV) dose of sarilumab) Other Name: Kevzara®, REGN88, SAR153191

Placebo

Drug: Placebo (Single intravenous (IV) dose of placebo to match sarilumab administration)

Results

Therapeutic efficacy

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 [2] .
2020-04-29 16:38:00.187

Adverse events

COVID-2019 Infections: Results from the phase II/III study showed no new safety findings were observed for sarilumab use in COVID-19 patients [2] .

Publications

  1. 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
  2. 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

Authors

Author Total Publications First Author Last Author
Regeneron Pharmaceuticals 1 1 -
Sanofi 2 1 2

Trial Centres

Investigators

Investigator Centre Name Trial Centre Country
Clinical Trials Administrator
844-734-6643 clinicaltrials@regeneron.com
show details
-

Centres

Centre Name Location Trial Centre Country
-
-
-
Regeneron Pharmaceuticals
Clinical Trials Administrator
844-734-6643
clinicaltrials@regeneron.com
show details
-
-
Regeneron Study Facility 2 Manhasset, New York USA
Regeneron Study Site Ann Arbor, Michigan USA
Regeneron Study Site Atlanta, Georgia USA
Regeneron Study Site Aurora, Colorado USA
Regeneron Study Site Baltimore, Maryland USA
Regeneron Study Site Boston, Massachusetts USA
Regeneron Study Site Bronx, New York USA
Regeneron Study Site Brooklyn, New York USA
Regeneron Study Site Chicago, Illinois USA
Regeneron Study Site Coral Gables, Florida 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 Detroit, Michigan 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 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 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 New York, New York USA
Regneron Study Site Boston, Massachusetts USA
Sanofi
-
-

Trial History

Event Date Event Type Comment
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
07 Apr 2020 Other trial event Last checked against Clinicaltrials.gov record. Updated 07 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. ClinicalTrials.gov: US National Institutes of Health. Trial-Reg 2016;.

    Available from: URL: http://clinicaltrials.gov
  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. 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
  4. Sanofi. Sanofi and Regeneron begin global Kevzara(Rm) (sarilumab) clinical trial program in patients with severe COVID-19. Media-Rel 2020;.

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

    Media Release
  6. 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
  7. 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
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