A Study to Evaluate the Safety and Efficacy of Tocilizumab in Patients With Severe COVID-19 Pneumonia

Phase 3

Completed

• Conditions: COVID-19 Pneumonia
• Interventions: Drug: Tocilizumab (TCZ); Drug: Placebo

• Registration Number: NCT04320615
• Lead Sponsor: Hoffmann-La Roche

Brief Summary

This study will evaluate the efficacy, safety, pharmacodynamics, and pharmacokinetics of tocilizumab (TCZ) compared with a matching placebo in combination with standard of care (SOC) in hospitalized patients with severe COVID-19 pneumonia.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2020-03-23
• Study First Submitted QC: 2020-03-23
• Study First Posted: 2020-03-25
• Study Start: 2020-04-03
• Primary Completion: 2020-06-24
• Study Completion: 2020-07-28
• Status Verified: 2021-06
• Results First Submitted: 2021-06-23
• Results First Submitted QC: 2021-06-28
• Last Update Submitted: 2021-06-28
• Results First Posted: 2021-06-30
• Last Update Posted: 2021-06-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 452

Inclusion Criteria

• Hospitalized with COVID-19 pneumonia confirmed per WHO criteria (including a positive PCR of any specimen; e.g., respiratory, blood, urine, stool, other bodily fluid) and evidenced by chest X-ray or CT scan
• SPO2 </=93% or PaO2/FiO2 <300 mmHg

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Exclusion Criteria

• Known severe allergic reactions to TCZ or other monoclonal antibodies
• Active tuberculosis (TB) infection
• Suspected active bacterial, fungal, viral, or other infection (besides COVID-19)
• In the opinion of the investigator, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments
• Have received oral anti-rejection or immunomodulatory drugs (including TCZ) with the past 3 months
• Participating in other drug clinical trials (participation in COVID-19 anti-viral trials may be permitted if approved by Medical Monitor)
• Pregnant or breastfeeding, or positive pregnancy test in a pre-dose examination
• Treatment with an investigational drug within 5 half-lives or 30 days (whichever is longer) of randomization (investigational COVID-19 antivirals may be permitted if approved by Medial Monitor)
• Any serious medical condition or abnormality of clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 10 x upper limit of normal (ULN) detected within 24 hours at screening (per local lab)
• Absolute neutrophil count (ANC) < 1000/mL at screening (per local lab)
• Platelet count < 50,000/mL at screening (per local lab)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tocilizumab (TCZ) Arm	Tocilizumab (TCZ)	Participants will receive 1 intravenous (IV) infusion of TCZ, dosed at 8 mg/kg, up to a maximum dose 800 mg. Up to 1 additional dose may be given if clinical symptoms worsen or show no improvement.
Placebo Arm	Placebo	Participants will receive 1 IV infusion of placebo matched to TCZ. Up to 1 additional dose may be given if clinical symptoms worsen or show no improvement.

Primary Outcome Measures

Name	Time	Method
Clinical Status Assessed Using a 7-Category Ordinal Scale at Day 28 (Week 4)	Day 28	Clinical status was assessed using a 7-category ordinal scale: 1. - Discharged (or "ready for discharge"); 2. - Non- intensive care unit (ICU) hospital ward (or "ready for hospital ward") not requiring supplemental oxygen; 3. - Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen; 4. - ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen; 5. - ICU, requiring intubation and mechanical ventilation; 6. - ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support; 7. - Death

Secondary Outcome Measures

Name	Time	Method
Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-Category Ordinal Scale of Clinical Status	Up to Day 28	Time to improvement for this outcome measure was defined as the days from the first dose of study drug to when at least a 2-category improvement in clinical status (based on a 7-category ordinal scale) is observed. Participants who died were censored at Day 28.
Time to Clinical Improvement (TTCI), Defined as a National Early Warning Score 2 (NEWS2) of </= 2 Maintained for 24 Hours	Up to Day 28	Defined as time from first dose of study drug to at least two NEWS2 assessments with a score of \<=2 covering a span of at least 21.5 hours, with a maximum of 26.5 hours between the first and last of these assessments and no assessments with a score \>2 in between. If one of the components of the NEWS2 score was missing at a particular time point, then the NEWS2 score was not calculated. Participants who died were censored at Day 28.
Time to Hospital Discharge or "Ready for Discharge"	Up to Day 28	Time to Hospital Discharge was defined as the time from the first dose of study drug to hospital discharge or "ready for discharge" (normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or \</=2L supplemental oxygen) Participants who died were censored at Day 28.
Incidence of Mechanical Ventilation by Day 28	Up to Day 28	Participants who died by Day 28 were assumed to have required mechanical ventilation.
Ventilator-Free Days to Day 28	Up to Day 28	Participants who died by Day 28 were assigned 0 ventilator-free days.
Incidence of Intensive Care Unit (ICU) Stay by Day 28 (Week 4)	Up to Day 28	Participants who died by Day 28 were assumed to have required an ICU stay.
Duration of ICU Stay to Day 28 (Week 4)	Up to Day 28	Participants who died by Day 28 were assigned a duration from the first dose of study drug to Day 28 at hour 23:59:59.
Clinical Status Assessed Using a 7-Category Ordinal Scale at Day 14	Day 14	Clinical status was assessed using a 7-category ordinal scale: 1. - Discharged (or "ready for discharge"); 2. - Non- intensive care unit (ICU) hospital ward (or "ready for hospital ward") not requiring supplemental oxygen; 3. - Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen; 4. - ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen; 5. - ICU, requiring intubation and mechanical ventilation; 6. - ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support; 7. - Death
Time to Clinical Failure to Day 28 (Week 4)	Up to Day 28	Time to clinical failure was defined as the number of days from the first dose of study drug to the first occurrence on study of death, mechanical ventilation, ICU admission, or study withdrawal prior to discharge, whichever occurs first.
Mortality Rate at Day 28 (Week 4)	Day 28
Time to Recovery to Day 28 (Week 4)	Up to Day 28	Time to recovery was defined as the number of days from the first dose of study drug to hospital discharge or "ready for discharge" (normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or \</= 2L supplemental oxygen) or non-ICU hospital ward or "ready for hospital ward" not requiring supplemental oxygen. Participants who died were censored at Day 28.
Duration of Supplemental Oxygen to Day 28 (Week 4)	Up to Day 28	Participants who died by Day 28 were assigned a duration of 28 days of supplemental oxygen.

Trial Locations

Locations (62)

Ochsner Clinic Foundation; 🇺🇸 Baton Rouge, Louisiana, United States

Robert Wood Johnson University Hospital/Rutgers; 🇺🇸 New Brunswick, New Jersey, United States

University Health Network; 🇨🇦 Toronto, Ontario, Canada

St. Antonius Ziekenhuis Nieuwegein; 🇳🇱 Nieuwegein, Netherlands

Erasmus MC; 🇳🇱 Rotterdam, Netherlands

Universitair Medisch Centrum Utrecht; 🇳🇱 Utrecht, Netherlands

Hackensack University Medical Center; 🇺🇸 Hackensack, New Jersey, United States

Rush University Medical Center; 🇺🇸 Chicago, Illinois, United States

University of Miami Miller School of Medicine; 🇺🇸 Miami, Florida, United States

Mayo Clinic - PPDS; 🇺🇸 Rochester, Minnesota, United States

James J Peters Veterans Administration Medical Center - NAVREF; 🇺🇸 Bronx, New York, United States

Intermountain Medical Group; 🇺🇸 Saint George, Utah, United States

Hôpital de La Croix Rousse; 🇫🇷 Lyon, France

CHRU de Tours, Pharmacie; 🇫🇷 Tours, France

Medizinische Hochschule Hannover; 🇩🇪 Hannover, Germany

Amphia Ziekenhuis; 🇳🇱 Breda, Netherlands

Azienda Ospedaliera San Gerardo di Monza; 🇮🇹 Monza MI, Lombardia, Italy

Fondazione IRCCS Policlinico San Matteo di Pavia; S.S. Fisiopatologia Respiratoria; 🇮🇹 Pavia, Lombardia, Italy

Hospital Universitari Vall d'Hebron; 🇪🇸 Barcelona, Spain

Hospital Universitario Ramon y Cajal; 🇪🇸 Madrid, Spain

Hospital General Universitario Gregorio Maranon; 🇪🇸 Madrid, Spain

University College Hospital; 🇬🇧 London, United Kingdom

Greater Glasgow and Clyde Health Board; 🇬🇧 Glasgow, United Kingdom

Leeds Teaching Hospitals NHS Trust; 🇬🇧 Leeds, United Kingdom

Royal Free Hospital; 🇬🇧 London, United Kingdom

St George's Clinical Research Facility; 🇬🇧 London, United Kingdom

North Manchester General Hospital; 🇬🇧 Manchester, United Kingdom

Hospital Universitario HM Sanchinarro-CIOCC; 🇪🇸 Madrid, Spain

Imperial College London; 🇬🇧 London, United Kingdom

Stanford University; 🇺🇸 Stanford, California, United States

University of California San Diego; 🇺🇸 La Jolla, California, United States

David Geffen School of Medicine UCLA; 🇺🇸 Los Angeles, California, United States

eStudySite; 🇺🇸 La Mesa, California, United States

University of Chicago; 🇺🇸 Chicago, Illinois, United States

Cleveland Clinic Foundation; Pulmonary, Allergy & Critical Care Medicine; 🇺🇸 Cleveland, Ohio, United States

Baystate Health System; 🇺🇸 Springfield, Massachusetts, United States

Baylor St. Luke's Medical Center; 🇺🇸 Houston, Texas, United States

Ben Taub General Hospital - HCHD; 🇺🇸 Houston, Texas, United States

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States

Intermountain LDS Hospital; 🇺🇸 Salt Lake City, Utah, United States

Evergreen Health Infectious Disease; 🇺🇸 Kirkland, Washington, United States

Hvidovre Hospital; 🇩🇰 Hvidovre, Denmark

Hamilton General Hospital; Pharmacy; 🇨🇦 Hamilton, Ontario, Canada

Rigshospitalet Copenhagen University Hospital; 🇩🇰 Copenhagen, Denmark

Clinical Research Institute of Montreal; 🇨🇦 Montreal, Quebec, Canada

Swedish Hospital Medical Center; 🇺🇸 Seattle, Washington, United States

Sjællands Universitetshospital, Roskilde; 🇩🇰 Roskilde, Denmark

Odense Universitetshospital; 🇩🇰 Odense C, Denmark

Centre Hospitalier Departemental de Vendee; 🇫🇷 La Roche Sur Yon, France

Centre Hospitalier et Universitaire de Limoges; 🇫🇷 Limoges, France

HOPITAL COCHIN university hospital; 🇫🇷 Paris, France

Hotel Dieu - Nantes; 🇫🇷 Nantes, France

Hopital de la Pitie Salpetriere; 🇫🇷 Paris, France

Universitatsklinikum Dusseldorf; 🇩🇪 Dusseldorf, Germany

Universitätsklinikum Köln; Innere Medizin I; Onkologie, Hämatologie; 🇩🇪 Köln, Germany

LMU Klinikum der Universitat Munchen; 🇩🇪 Munchen, Germany

Hospital Universitario de Bellvitge; 🇪🇸 Hospitalet de Llobregat, Barcelona, Spain

Hospital Universitario La Paz; 🇪🇸 Madrid, Spain

Hospital Clinic de Barcelona; 🇪🇸 Barcelona, Spain

Denver Health Medical Center; 🇺🇸 Denver, Colorado, United States

Thomas Jefferson University; 🇺🇸 Philadelphia, Pennsylvania, United States

St. Joseph's Healthcare Hamilton; 🇨🇦 Hamilton, Ontario, Canada