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

A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of Tocilizumab in Patients With Severe COVID-19 Pneumonia

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.

Study Overview

• Status: Completed
• Conditions: COVID-19 Pneumonia
• Intervention / Treatment: Drug: Tocilizumab (TCZ); Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 452
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 4A6
      • St. Joseph's Healthcare Hamilton
    • Hamilton, Ontario, Canada, L8L 2X2
      • Hamilton General Hospital; Pharmacy
    • Toronto, Ontario, Canada, M5G2M9
      • University Health Network
  • Quebec
    • Montreal, Quebec, Canada, H2W 1R7
      • Clinical Research Institute of Montreal
• Denmark
  • Copenhagen, Denmark, DK-2100
    • Rigshospitalet Copenhagen University Hospital
  • Hvidovre, Denmark, DK-2650
    • Hvidovre Hospital
  • Odense C, Denmark, 5000
    • Odense Universitetshospital
  • Roskilde, Denmark, 4000
    • Sjællands Universitetshospital, Roskilde
• France
  • La Roche Sur Yon, France, 85925
    • Centre Hospitalier Départemental de Vendée
  • Limoges, France, 87042
    • Centre Hospitalier Et Universitaire De Limoges
  • Lyon, France, 69004
    • Hôpital de la Croix Rousse
  • Nantes, France, 44093
    • Hotel Dieu - Nantes
  • Paris, France, 75013
    • Hopital de la Pitie Salpetriere
  • Paris, France, 75014
    • HOPITAL COCHIN university hospital
  • Tours, France, 37044
    • CHRU de Tours, Pharmacie
• Germany
  • Dusseldorf, Germany, 40225
    • Universitatsklinikum Dusseldorf
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Köln, Germany, 50931
    • Universitätsklinikum Köln; Innere Medizin I; Onkologie, Hämatologie
  • Munchen, Germany, 80337
    • LMU Klinikum der Universität München
• Italy
  • Lombardia
    • Monza MI, Lombardia, Italy, 20900
      • Azienda Ospedaliera San Gerardo di Monza
    • Pavia, Lombardia, Italy, 27100
      • Fondazione IRCCS Policlinico San Matteo di Pavia; S.S. Fisiopatologia Respiratoria
• Netherlands
  • Breda, Netherlands, 4819 EV
    • Amphia Ziekenhuis
  • Nieuwegein, Netherlands, 3435 CM
    • St. Antonius Ziekenhuis Nieuwegein
  • Rotterdam, Netherlands, 3015 GD
    • Erasmus MC
  • Utrecht, Netherlands, 3584 CX
    • Universitair Medisch Centrum Utrecht
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic de Barcelona
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Madrid, Spain, 28040
    • Hospital General Universitario Gregorio Marañon
  • Madrid, Spain, 28034
    • Hospital Universitario La Paz
  • Madrid, Spain, 28050
    • Hospital Universitario HM Sanchinarro-CIOCC
  • Barcelona
    • Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Hospital Universitario de Bellvitge
• United Kingdom
  • Glasgow, United Kingdom, G12 8TA
    • Greater Glasgow and Clyde Health Board
  • Leeds, United Kingdom, LS9 7AU
    • Leeds Teaching Hospitals NHS Trust
  • London, United Kingdom, NW1 2BU
    • University College Hospital
  • London, United Kingdom, NW3 2QS
    • Royal Free Hospital
  • London, United Kingdom, SW17 0RE
    • St George's Clinical Research Facility
  • London, United Kingdom, W6 8RF
    • Imperial College London
  • Manchester, United Kingdom, M8 5RB
    • North Manchester General Hospital
• United States
  • California
    • La Jolla, California, United States, 92093
      • University Of California San Diego
    • La Mesa, California, United States, 91942
      • eStudySite
    • Los Angeles, California, United States, 90095
      • David Geffen School of Medicine UCLA
    • Stanford, California, United States, 94305
      • Stanford University
  • Colorado
    • Denver, Colorado, United States, 80204
      • Denver Health Medical Center
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Ochsner Clinic Foundation
  • Massachusetts
    • Springfield, Massachusetts, United States, 01199
      • Baystate Health System
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic - PPDS
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
    • New Brunswick, New Jersey, United States, 08901
      • Robert Wood Johnson University Hospital/Rutgers
  • New York
    • Bronx, New York, United States, 10468
      • James J Peters Veterans Administration Medical Center - NAVREF
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation; Pulmonary, Allergy & Critical Care Medicine
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor St. Luke's Medical Center
    • Houston, Texas, United States, 77030
      • Ben Taub General Hospital - HCHD
  • Utah
    • Saint George, Utah, United States, 84770
      • Intermountain Medical Group
    • Salt Lake City, Utah, United States, 84143
      • Intermountain LDS Hospital
  • Washington
    • Kirkland, Washington, United States, 98034
      • Evergreen Health Infectious Disease
    • Seattle, Washington, United States, 98104
      • Swedish Hospital Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Tocilizumab (TCZ) Arm; 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.	Drug: Tocilizumab (TCZ); Participants will receive 1 dose of IV TCZ. 1 additional dose may be given if clinical symptoms worsen or show no improvement.
PLACEBO_COMPARATOR: Placebo Arm; 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.	Drug: Placebo; Participants will receive 1 dose of IV placebo matched to TCZ. Up to 1 additional dose may be given if clinical symptoms worsen or show no improvement.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Clinical Improvement (TTCI), Defined as a National Early Warning Score 2 (NEWS2) of </= 2 Maintained for 24 Hours	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.	Up to Day 28
Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-Category Ordinal Scale of Clinical Status	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.	Up to Day 28
Time to Hospital Discharge or "Ready for Discharge"	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.	Up to Day 28
Incidence of Mechanical Ventilation by Day 28	Participants who died by Day 28 were assumed to have required mechanical ventilation.	Up to Day 28
Ventilator-Free Days to Day 28	Participants who died by Day 28 were assigned 0 ventilator-free days.	Up to Day 28
Incidence of Intensive Care Unit (ICU) Stay by Day 28 (Week 4)	Participants who died by Day 28 were assumed to have required an ICU stay.	Up to Day 28
Duration of ICU Stay to Day 28 (Week 4)	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.	Up to Day 28
Clinical Status Assessed Using a 7-Category Ordinal Scale at Day 14	Clinical status was assessed using a 7-category ordinal scale: - Discharged (or "ready for discharge"); - Non- intensive care unit (ICU) hospital ward (or "ready for hospital ward") not requiring supplemental oxygen; - Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen; - ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen; - ICU, requiring intubation and mechanical ventilation; - ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support; - Death	Day 14
Time to Clinical Failure to Day 28 (Week 4)	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.	Up to Day 28
Mortality Rate at Day 28 (Week 4)		Day 28
Time to Recovery to Day 28 (Week 4)	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.	Up to Day 28
Duration of Supplemental Oxygen to Day 28 (Week 4)	Participants who died by Day 28 were assigned a duration of 28 days of supplemental oxygen.	Up to Day 28

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Rosas IO, Brau N, Waters M, Go RC, Malhotra A, Hunter BD, Bhagani S, Skiest D, Savic S, Douglas IS, Garcia-Diaz J, Aziz MS, Cooper N, Youngstein T, Sorbo LD, Zerda DJ, Ustianowski A, Gracian AC, Blyth KG, Carratala J, Francois B, Benfield T, Haslem D, Bonfanti P, van der Leest CH, Rohatgi N, Wiese L, Luyt CE, Bauer RN, Cai F, Lee IT, Matharu B, Metcalf L, Wildum S, Graham E, Tsai L, Bao M. Tocilizumab in patients hospitalised with COVID-19 pneumonia: Efficacy, safety, viral clearance, and antibody response from a randomised controlled trial (COVACTA). EClinicalMedicine. 2022 May;47:101409. doi: 10.1016/j.eclinm.2022.101409. Epub 2022 Apr 21.
• Tom J, Bao M, Tsai L, Qamra A, Summers D, Carrasco-Triguero M, McBride J, Rosenberger CM, Lin CJF, Stubbings W, Blyth KG, Carratala J, Francois B, Benfield T, Haslem D, Bonfanti P, van der Leest CH, Rohatgi N, Wiese L, Luyt CE, Kheradmand F, Rosas IO, Cai F. Prognostic and Predictive Biomarkers in Patients With Coronavirus Disease 2019 Treated With Tocilizumab in a Randomized Controlled Trial. Crit Care Med. 2022 Mar 1;50(3):398-409. doi: 10.1097/CCM.0000000000005229.
• Rosas IO, Brau N, Waters M, Go RC, Hunter BD, Bhagani S, Skiest D, Aziz MS, Cooper N, Douglas IS, Savic S, Youngstein T, Del Sorbo L, Cubillo Gracian A, De La Zerda DJ, Ustianowski A, Bao M, Dimonaco S, Graham E, Matharu B, Spotswood H, Tsai L, Malhotra A. Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia. N Engl J Med. 2021 Apr 22;384(16):1503-1516. doi: 10.1056/NEJMoa2028700. Epub 2021 Feb 25.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 3, 2020
• Primary Completion (ACTUAL): June 24, 2020
• Study Completion (ACTUAL): July 28, 2020

Study Registration Dates

• First Submitted: March 23, 2020
• First Submitted That Met QC Criteria: March 23, 2020
• First Posted (ACTUAL): March 25, 2020

Study Record Updates

• Last Update Posted (ACTUAL): June 30, 2021
• Last Update Submitted That Met QC Criteria: June 28, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Lung Diseases; COVID-19; Pneumonia
• Other Study ID Numbers: WA42380; 2020-001154-22 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers may request access to individual patient level data through the clinical study data request platform https://vivli.org.

Further details on Roche's criteria for eligible studies are available here: https://vivli.org.

For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here: (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No