Efficacy of Early Administration of Tocilizumab in COVID-19 Patients

An Open-label Randomized Multicenter Study to Evaluate the Efficacy of Early Administration of Tocilizumab (TCZ) in Patients With COVID-19 Pneumonia

The clinical study aims at assessing whether early administration of Tocilizumab compared to late administration of Tocilizumab can reduce the number of patients with COVID-19 pneumonia who require mechanical ventilation. The clinical study includes patients with recent-onset COVID-19 pneumonia who require hospital care, but not invasive or semi-invasive mechanical ventilation procedures.

Study Overview

• Status: Terminated
• Conditions: COVID-19 Pneumonia
• Intervention / Treatment: Drug: Tocilizumab

• Study Type: Interventional
• Enrollment (Actual): 126
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Alessandria, Italy
    • Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo
  • Bologna, Italy
    • Policlinico Sant'Orsola Malpighi
  • Cremona, Italy
    • ASST Cremona
  • Cuneo, Italy
    • Azienda Ospedaliera S. Croce e Carle
  • Ferrara, Italy
    • Azienda Ospedaliero Universitaria Ferrara
  • Firenze, Italy
    • Azienda Ospedaliero Universitaria Careggi
  • Genova, Italy
    • Ospedale Evangelico Internazionale di Genova
  • Imperia, Italy
    • Azienda Sociosanitaria ASL 1 ,Imperia
  • La Spezia, Italy
    • Azienda Sociosanitaria ASL 5 La Spezia
  • Mantova, Italy
    • ASST Mantova - Ospedale Carlo Poma
  • Milano, Italy
    • IRCCS Istituto Auxologico Italiano Milano
  • Novara, Italy
    • Azienda Ospedaliero-Universitaria "Maggiore della Carità" di Novara
  • Padova, Italy
    • Ospedali Riuniti Padova Sud - ULSS 6 Euganea
  • Parma, Italy
    • Azienda Ospedaliero-Universitaria Parma
  • Piacenza, Italy
    • Azienda Unita Sanitaria Locale di Piacenza
  • Pisa, Italy
    • Azienda Ospedaliera Universitaria Pisana
  • Torino, Italy
    • AO Ordine Mauriziano di Torino
  • Treviglio, Italy
    • ASST Bergamo Ovest -Treviglio
  • Treviso, Italy
    • AULSS 2 Marca Trevigiana
  • Treviso, Italy
    • AULSS2 Marca Trevigiana - Ospedale Vittorio Veneto
  • Venezia, Italy
    • AULSS 3 Serenissima Ospedale "Dell'Angelo"
  • Verona, Italy
    • Azienda Ospedaliera Universitaria Integrata di Verona
  • Verona, Italy
    • IRCCS Sacro Cuore Don Calabria
  • RE
    • Guastalla, RE, Italy
      • Ospedale di Guastalla
    • Reggio Emilia, RE, Italy, 42122
      • Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia

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:

• age > 18 years
• Informed consent for participation in the study
• Real time polymerase chain reaction (PCR) diagnosis of Sars-CoV2 infection
• Hospitalization due to clinical / instrumental diagnosis (high resolution chest CT scan or chest x-ray or pulmonary ultrasound)
• Presence of acute respiratory distress syndrome with arterial partial pressure of oxygen / fraction of inspired oxygen (PaO2 / FiO2) between 200 and 300 mm/Hg
• Presence of exaggerated inflammatory response defined by the presence of at least 1 of the following criteria:
• At least one body temperature measurement >38° C in the past two days;
• Serum CRP greater than or equal to 10 mg/dl;
• CRP increase of at least twice the basal value

Exclusion Criteria:

• Patients with respiratory distress syndrome with arterial partial pressure of oxygen / fraction of inspired oxygen (PaO2 / FiO2) <200 mm/Hg or
• Patients in non-invasive ventilation or
• Patients in invasive ventilation or presence of shock or presence of concomitant organ failure that requires admission to the Intensive Care Unit
• Severe heart and kidney failure
• Pregnant or breastfeeding patient
• Patient who, in the opinion of the clinician or by the patient's express will, will not go to intensive care regardless of the evolution of the lung picture.
• Known hypersensitivity to TCZ or its excipients
• Patient being treated with immuno-depressors or anti-rejection drugs
• Known active infections or other clinical conditions that contraindicate TCZ and cannot be treated or resolved according to the physician's judgment
• glutamate-pyruvate transaminase (GPT) or glutamine oxaloacetic transaminase (GOT) > 5 times the upper limit of the norm
• Neutrophils <500 /mmc
• Platelets <50.000 /mmc
• Diverticulitis or intestinal perforation
• Suspicion of latent tuberculosis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental Arm; Tocilizumab within 8 hours from entering the study + standard of care; 8 mg/kg IV up to a maximum of 800 mg with repetition of the same dosage after 12 hours	Drug: Tocilizumab; In case of aggravation of COVID-19 pneumonia, according to protocol criteria, participants will receive 8 mg/kg IV up to a maximum of 800 mg with repetition of the same dosage after 12 hours; Other Names: Standard of care
Other: Control Arm; Standard of care; In the event of aggravation of COVID-19 pneumonia, according to protocol criteria, participants will receive 8 mg/kg IV up to a maximum of 800 mg with repetition of the same dosage after 12 hours	Drug: Tocilizumab; In case of aggravation of COVID-19 pneumonia, according to protocol criteria, participants will receive 8 mg/kg IV up to a maximum of 800 mg with repetition of the same dosage after 12 hours; Other Names: Standard of care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Entry into Intensive Care with invasive mechanical ventilation or death from any cause or clinical aggravation	Entry into Intensive Care with invasive mechanical ventilation or death from any cause or clinical aggravation documented by the finding of a PaO2 / FiO2 ratio <150mm / Hg confirmed by a second arterial blood gas (ABG) measurement within four hours	two weeks from participants' allocation to study arm

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death from any cause	Death	Two weeks from participants' allocation to study arm
Tocilizumab toxicity	Adverse events (AE) classified according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) scale	Two weeks from participants' allocation to study arm
Levels of interleukin-6 and C-reactive protein (CRP) and their correlation with the effectiveness of the treatment	Levels of ferritin, lactate dehydrogenase and D-dimer and their correlation with the effectiveness of the treatment	Two weeks from participants' allocation to study arm
Evaluate the progress of the PaO2 / FiO2 ratio	Changes from baseline of the PaO2 / FiO2 ratio	Two weeks from participants' allocation to study arm
Evaluate the trend over time of the lymphocyte count	Changes from baseline of the lymphocyte count	Two weeks from participants' allocation to study arm

Collaborators and Investigators

• Sponsor: Azienda Unita Sanitaria Locale Reggio Emilia
• Investigators: Study Director: Carlo Salvarani, M.D., Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia; Study Director: Massimo Costantini, Ph.D., Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia

Publications and helpful links

General Publications

• Salvarani C, Dolci G, Massari M, Merlo DF, Cavuto S, Savoldi L, Bruzzi P, Boni F, Braglia L, Turra C, Ballerini PF, Sciascia R, Zammarchi L, Para O, Scotton PG, Inojosa WO, Ravagnani V, Salerno ND, Sainaghi PP, Brignone A, Codeluppi M, Teopompi E, Milesi M, Bertomoro P, Claudio N, Salio M, Falcone M, Cenderello G, Donghi L, Del Bono V, Colombelli PL, Angheben A, Passaro A, Secondo G, Pascale R, Piazza I, Facciolongo N, Costantini M; RCT-TCZ-COVID-19 Study Group. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2021 Jan 1;181(1):24-31. doi: 10.1001/jamainternmed.2020.6615.

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2020
• Primary Completion (Actual): June 6, 2020
• Study Completion (Actual): June 6, 2020

Study Registration Dates

• First Submitted: April 12, 2020
• First Submitted That Met QC Criteria: April 14, 2020
• First Posted (Actual): April 15, 2020

Study Record Updates

• Last Update Posted (Actual): June 22, 2020
• Last Update Submitted That Met QC Criteria: June 18, 2020
• Last Verified: June 1, 2020

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: RCT-TCZ-COVID-19; 2020-001386-37 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No