Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial - PubMed (original) (raw)

Randomized Controlled Trial

. 2021 Jan 1;181(1):24-31.

doi: 10.1001/jamainternmed.2020.6615.

Giovanni Dolci 3, Marco Massari 4, Domenico Franco Merlo 5, Silvio Cavuto 5, Luisa Savoldi 5, Paolo Bruzzi 6, Fabrizio Boni 7, Luca Braglia 5, Caterina Turrà 8, Pier Ferruccio Ballerini 9, Roberto Sciascia 9, Lorenzo Zammarchi 10, Ombretta Para 11, Pier Giorgio Scotton 12, Walter Omar Inojosa 12, Viviana Ravagnani 13, Nicola Duccio Salerno 14, Pier Paolo Sainaghi 15, Alessandro Brignone 16, Mauro Codeluppi 17, Elisabetta Teopompi 7, Maurizio Milesi 18, Perla Bertomoro 19, Norbiato Claudio 20, Mario Salio 21, Marco Falcone 22, Giovanni Cenderello 23, Lorenzo Donghi 24, Valerio Del Bono 25, Paolo Luigi Colombelli 26, Andrea Angheben 27, Angelina Passaro 28, Giovanni Secondo 29, Renato Pascale 30, Ilaria Piazza 31, Nicola Facciolongo 32, Massimo Costantini 33; RCT-TCZ-COVID-19 Study Group

Affiliations

Randomized Controlled Trial

Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial

Carlo Salvarani et al. JAMA Intern Med. 2021.

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.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Drs Massari, Merlo, and Costantini, Mr Cavuto, and Mss Savoldi and Turrà reported receiving nonfinancial support (provision of experimental drug and distribution to clinical sites) from Roche during the conduct of the study. Dr Falcone reported receiving speaker fees from Angelini, Merck Sharp & Dohme, Pfizer, Nordic Pharma, and Shionogi outside the submitted work. Dr Angheben reported receiving grants from Italian Ministry of Health during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.

Figure 1.. Flowchart of the Study

IV indicates intravenous.

Figure 2.

Figure 2.. Kaplan-Meier Estimates of Cumulative Clinical Worsening and Hospital Discharge

Kaplan-Meier estimates of cumulative clinical worsening (A) and hospital discharge (B).

Comment in

Similar articles

Cited by

References

    1. Guan W-J, Ni Z-Y, Hu Y, et al. ; China Medical Treatment Expert Group for Covid-19 . Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708-1720. doi:10.1056/NEJMoa2002032 - DOI - PMC - PubMed
    1. Huang C, Wang Y, Li X, et al. . Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. doi:10.1016/S0140-6736(20)30183-5 - DOI - PMC - PubMed
    1. Qin C, Zhou L, Hu Z, et al. . Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis. 2020;71(15):762-768. doi:10.1093/cid/ciaa248 - DOI - PMC - PubMed
    1. Chen G, Wu D, Guo W, et al. . Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130(5):2620-2629. doi:10.1172/JCI137244 - DOI - PMC - PubMed
    1. Cao X. COVID-19: immunopathology and its implications for therapy. Nat Rev Immunol. 2020;20(5):269-270. doi:10.1038/s41577-020-0308-3 - DOI - PMC - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources