Tags

Type your tag names separated by a space and hit enter

Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.
JAMA Intern Med. 2021 01 01; 181(1):24-31.JIM

Abstract

Importance

The coronavirus disease 2019 (COVID-19) pandemic is threatening billions of people worldwide. Tocilizumab has shown promising results in retrospective studies in patients with COVID-19 pneumonia with a good safety profile.

Objective

To evaluate the effect of early tocilizumab administration vs standard therapy in preventing clinical worsening in patients hospitalized with COVID-19 pneumonia.

Design, Setting, and Participants

Prospective, open-label, randomized clinical trial that randomized patients hospitalized between March 31 and June 11, 2020, with COVID-19 pneumonia to receive tocilizumab or standard of care in 24 hospitals in Italy. Cases of COVID-19 were confirmed by polymerase chain reaction method with nasopharyngeal swab. Eligibility criteria included COVID-19 pneumonia documented by radiologic imaging, partial pressure of arterial oxygen to fraction of inspired oxygen (Pao2/Fio2) ratio between 200 and 300 mm Hg, and an inflammatory phenotype defined by fever and elevated C-reactive protein.

Interventions

Patients in the experimental arm received intravenous tocilizumab within 8 hours from randomization (8 mg/kg up to a maximum of 800 mg), followed by a second dose after 12 hours. Patients in the control arm received supportive care following the protocols of each clinical center until clinical worsening and then could receive tocilizumab as a rescue therapy.

Main Outcome and Measures

The primary composite outcome was defined as entry into the intensive care unit with invasive mechanical ventilation, death from all causes, or clinical aggravation documented by the finding of a Pao2/Fio2 ratio less than 150 mm Hg, whichever came first.

Results

A total of 126 patients were randomized (60 to the tocilizumab group; 66 to the control group). The median (interquartile range) age was 60.0 (53.0-72.0) years, and the majority of patients were male (77 of 126, 61.1%). Three patients withdrew from the study, leaving 123 patients available for the intention-to-treat analyses. Seventeen patients of 60 (28.3%) in the tocilizumab arm and 17 of 63 (27.0%) in the standard care group showed clinical worsening within 14 days since randomization (rate ratio, 1.05; 95% CI, 0.59-1.86). Two patients in the experimental group and 1 in the control group died before 30 days from randomization, and 6 and 5 patients were intubated in the 2 groups, respectively. The trial was prematurely interrupted after an interim analysis for futility.

Conclusions and Relevance

In this randomized clinical trial of hospitalized adult patients with COVID-19 pneumonia and Pao2/Fio2 ratio between 200 and 300 mm Hg who received tocilizumab, no benefit on disease progression was observed compared with standard care. Further blinded, placebo-controlled randomized clinical trials are needed to confirm the results and to evaluate possible applications of tocilizumab in different stages of the disease.

Trial Registration

ClinicalTrials.gov Identifier: NCT04346355; EudraCT Identifier: 2020-001386-37.

Authors+Show Affiliations

SOC Reumatologia, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy. Unità di Reumatologia, Università degli Studi di Modena e Reggio Emilia, Reggio Emilia, Italy.Unità di Malattie Infettive, Università degli Studi di Modena e Reggio Emilia, Reggio Emilia, Italy.SOC Malattie Infettive, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.SC Infrastruttura Ricerca e Statistica, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.SC Infrastruttura Ricerca e Statistica, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.SC Infrastruttura Ricerca e Statistica, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.SC Epidemiologia Clinica, IRCCS Ospedale Policlinico San Martino, Genova, Italy.SOC Internistica Multidisciplinare, Ospedale Civile Guastalla, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.SC Infrastruttura Ricerca e Statistica, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.SOC Farmacia, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.UOC Medicina Generale Ospedale di Vittorio Veneto, Treviso, Italy.UOC Medicina Generale Ospedale di Vittorio Veneto, Treviso, Italy.Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Firenze, SOD Malattie infettive e tropicali, AOU Careggi, Firenze, Italy.Medicina Interna 1, Dipartimento Emergenza ed Accettazione, AOU Careggi, Firenze, Italy.UO di Malattie Infettive, Ospedale Regionale Ca' Foncello di Treviso, Treviso, Italy.UO di Malattie Infettive, Ospedale Regionale Ca' Foncello di Treviso, Treviso, Italy.SSD Centro DH Allergologia e Immunologia Clinica, ASST-Mantova, Mantva, Italy.UOC Malattie Infettive e Tropicali, AOUI di Verona, Verona, Italy.SS Reumatologia, SC Medicina Interna, DIMET, Università del Piemonte Orientale e AOU Maggiore della Carità di Novara.Reumatologia, Medicina Interna, Ospedale S. Andrea, La Spezia, Italy.UOC Malattie Infettive, AUSL di Piacenza, Piacenza, Italy.SOC Internistica Multidisciplinare, Ospedale Civile Guastalla, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.Unità di malattie Infettive, ASST di Cremona, Cremona, Italy.UOC Medicina Generale, ULSS6 Euganea Ospedali Riuniti Padova Sud, Padova, Italy.SC Medicina Interna, AO Ordine Mauriziano, Torino, Italy.SC Malattie dell'Apparato Respiratorio, AO SS. Antonio e Biagio e C. Arrigo, Alessandria, Italy.Unità di Malattie Infettive, Dipartimento di Medicina Clinica e Sperimentale, Università di Pisa, Pisa, Italy.SC Malattie Infettive, ASL1 Imperia, Impersia, Italy.UO Malattie Infettive ed Epatologia, AOU Parma, Parma, Italy.Malattie Infettive e Tropicali, AO S. Croce e Carle, Cuneo, Italy.UO Medicina, Ospedale di Treviglio, ASST Bergamo Ovest, Bergamo, Italy.Dipartimento di Malattie Infettive, Tropicali e Microbiologia, IRCCS Ospedale Sacro Cuore-Don Calabria, Negrar di Valpolicella, Verona, Italy.Medicina Interna Universitaria, AOU Ferrara, Ferrara, Italy.Medicina Interna, Ospedale Evangelico, Genoa, Italy.UO Malattie Infettive, Dipartimento di scienze mediche e chirurgiche, Università di Bologna, Bologna, Italy.UOC Medicina Interna, AUSSS3 Serenissima, Dolo, Venezia, Italy.SOC Pneumologia, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.No affiliation info available

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33080005

Citation

Salvarani, Carlo, et al. "Effect of Tocilizumab Vs Standard Care On Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: a Randomized Clinical Trial." JAMA Internal Medicine, vol. 181, no. 1, 2021, pp. 24-31.
Salvarani C, Dolci G, Massari M, et al. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2021;181(1):24-31.
Salvarani, C., Dolci, G., Massari, M., Merlo, D. F., Cavuto, S., Savoldi, L., Bruzzi, P., Boni, F., Braglia, L., Turrà, C., Ballerini, P. F., Sciascia, R., Zammarchi, L., Para, O., Scotton, P. G., Inojosa, W. O., Ravagnani, V., Salerno, N. D., Sainaghi, P. P., ... Costantini, M. (2021). Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. JAMA Internal Medicine, 181(1), 24-31. https://doi.org/10.1001/jamainternmed.2020.6615
Salvarani C, et al. Effect of Tocilizumab Vs Standard Care On Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: a Randomized Clinical Trial. JAMA Intern Med. 2021 01 1;181(1):24-31. PubMed PMID: 33080005.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. AU - Salvarani,Carlo, AU - Dolci,Giovanni, AU - Massari,Marco, AU - Merlo,Domenico Franco, AU - Cavuto,Silvio, AU - Savoldi,Luisa, AU - Bruzzi,Paolo, AU - Boni,Fabrizio, AU - Braglia,Luca, AU - Turrà,Caterina, AU - Ballerini,Pier Ferruccio, AU - Sciascia,Roberto, AU - Zammarchi,Lorenzo, AU - Para,Ombretta, AU - Scotton,Pier Giorgio, AU - Inojosa,Walter Omar, AU - Ravagnani,Viviana, AU - Salerno,Nicola Duccio, AU - Sainaghi,Pier Paolo, AU - Brignone,Alessandro, AU - Codeluppi,Mauro, AU - Teopompi,Elisabetta, AU - Milesi,Maurizio, AU - Bertomoro,Perla, AU - Claudio,Norbiato, AU - Salio,Mario, AU - Falcone,Marco, AU - Cenderello,Giovanni, AU - Donghi,Lorenzo, AU - Del Bono,Valerio, AU - Colombelli,Paolo Luigi, AU - Angheben,Andrea, AU - Passaro,Angelina, AU - Secondo,Giovanni, AU - Pascale,Renato, AU - Piazza,Ilaria, AU - Facciolongo,Nicola, AU - Costantini,Massimo, AU - ,, PY - 2020/10/21/pubmed PY - 2021/1/16/medline PY - 2020/10/20/entrez SP - 24 EP - 31 JF - JAMA internal medicine JO - JAMA Intern Med VL - 181 IS - 1 N2 - Importance: The coronavirus disease 2019 (COVID-19) pandemic is threatening billions of people worldwide. Tocilizumab has shown promising results in retrospective studies in patients with COVID-19 pneumonia with a good safety profile. Objective: To evaluate the effect of early tocilizumab administration vs standard therapy in preventing clinical worsening in patients hospitalized with COVID-19 pneumonia. Design, Setting, and Participants: Prospective, open-label, randomized clinical trial that randomized patients hospitalized between March 31 and June 11, 2020, with COVID-19 pneumonia to receive tocilizumab or standard of care in 24 hospitals in Italy. Cases of COVID-19 were confirmed by polymerase chain reaction method with nasopharyngeal swab. Eligibility criteria included COVID-19 pneumonia documented by radiologic imaging, partial pressure of arterial oxygen to fraction of inspired oxygen (Pao2/Fio2) ratio between 200 and 300 mm Hg, and an inflammatory phenotype defined by fever and elevated C-reactive protein. Interventions: Patients in the experimental arm received intravenous tocilizumab within 8 hours from randomization (8 mg/kg up to a maximum of 800 mg), followed by a second dose after 12 hours. Patients in the control arm received supportive care following the protocols of each clinical center until clinical worsening and then could receive tocilizumab as a rescue therapy. Main Outcome and Measures: The primary composite outcome was defined as entry into the intensive care unit with invasive mechanical ventilation, death from all causes, or clinical aggravation documented by the finding of a Pao2/Fio2 ratio less than 150 mm Hg, whichever came first. Results: A total of 126 patients were randomized (60 to the tocilizumab group; 66 to the control group). The median (interquartile range) age was 60.0 (53.0-72.0) years, and the majority of patients were male (77 of 126, 61.1%). Three patients withdrew from the study, leaving 123 patients available for the intention-to-treat analyses. Seventeen patients of 60 (28.3%) in the tocilizumab arm and 17 of 63 (27.0%) in the standard care group showed clinical worsening within 14 days since randomization (rate ratio, 1.05; 95% CI, 0.59-1.86). Two patients in the experimental group and 1 in the control group died before 30 days from randomization, and 6 and 5 patients were intubated in the 2 groups, respectively. The trial was prematurely interrupted after an interim analysis for futility. Conclusions and Relevance: In this randomized clinical trial of hospitalized adult patients with COVID-19 pneumonia and Pao2/Fio2 ratio between 200 and 300 mm Hg who received tocilizumab, no benefit on disease progression was observed compared with standard care. Further blinded, placebo-controlled randomized clinical trials are needed to confirm the results and to evaluate possible applications of tocilizumab in different stages of the disease. Trial Registration: ClinicalTrials.gov Identifier: NCT04346355; EudraCT Identifier: 2020-001386-37. SN - 2168-6114 UR - https://www.unboundmedicine.com/medline/citation/33080005/Effect_of_Tocilizumab_vs_Standard_Care_on_Clinical_Worsening_in_Patients_Hospitalized_With_COVID_19_Pneumonia:_A_Randomized_Clinical_Trial_ L2 - https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/10.1001/jamainternmed.2020.6615 DB - PRIME DP - Unbound Medicine ER -