tetano
Editor, Senior Moderator
JAMA Intern Med
. 2020 Oct 20.
doi: 10.1001/jamainternmed.2020.6615. Online ahead of print.
Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial
Carlo Salvarani[SUP] 1 2 [/SUP], Giovanni Dolci[SUP] 3 [/SUP], Marco Massari[SUP] 4 [/SUP], Domenico Franco Merlo[SUP] 5 [/SUP], Silvio Cavuto[SUP] 5 [/SUP], Luisa Savoldi[SUP] 5 [/SUP], Paolo Bruzzi[SUP] 6 [/SUP], Fabrizio Boni[SUP] 7 [/SUP], Luca Braglia[SUP] 5 [/SUP], Caterina Turr?[SUP] 8 [/SUP], Pier Ferruccio Ballerini[SUP] 9 [/SUP], Roberto Sciascia[SUP] 9 [/SUP], Lorenzo Zammarchi[SUP] 10 [/SUP], Ombretta Para[SUP] 11 [/SUP], Pier Giorgio Scotton[SUP] 12 [/SUP], Walter Omar Inojosa[SUP] 12 [/SUP], Viviana Ravagnani[SUP] 13 [/SUP], Nicola Duccio Salerno[SUP] 14 [/SUP], Pier Paolo Sainaghi[SUP] 15 [/SUP], Alessandro Brignone[SUP] 16 [/SUP], Mauro Codeluppi[SUP] 17 [/SUP], Elisabetta Teopompi[SUP] 7 [/SUP], Maurizio Milesi[SUP] 18 [/SUP], Perla Bertomoro[SUP] 19 [/SUP], Norbiato Claudio[SUP] 20 [/SUP], Mario Salio[SUP] 21 [/SUP], Marco Falcone[SUP] 22 [/SUP], Giovanni Cenderello[SUP] 23 [/SUP], Lorenzo Donghi[SUP] 24 [/SUP], Valerio Del Bono[SUP] 25 [/SUP], Paolo Luigi Colombelli[SUP] 26 [/SUP], Andrea Angheben[SUP] 27 [/SUP], Angelina Passaro[SUP] 28 [/SUP], Giovanni Secondo[SUP] 29 [/SUP], Renato Pascale[SUP] 30 [/SUP], Ilaria Piazza[SUP] 31 [/SUP], Nicola Facciolongo[SUP] 32 [/SUP], Massimo Costantini[SUP] 33 [/SUP], RCT-TCZ-COVID-19 Study Group
Affiliations
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.
. 2020 Oct 20.
doi: 10.1001/jamainternmed.2020.6615. Online ahead of print.
Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial
Carlo Salvarani[SUP] 1 2 [/SUP], Giovanni Dolci[SUP] 3 [/SUP], Marco Massari[SUP] 4 [/SUP], Domenico Franco Merlo[SUP] 5 [/SUP], Silvio Cavuto[SUP] 5 [/SUP], Luisa Savoldi[SUP] 5 [/SUP], Paolo Bruzzi[SUP] 6 [/SUP], Fabrizio Boni[SUP] 7 [/SUP], Luca Braglia[SUP] 5 [/SUP], Caterina Turr?[SUP] 8 [/SUP], Pier Ferruccio Ballerini[SUP] 9 [/SUP], Roberto Sciascia[SUP] 9 [/SUP], Lorenzo Zammarchi[SUP] 10 [/SUP], Ombretta Para[SUP] 11 [/SUP], Pier Giorgio Scotton[SUP] 12 [/SUP], Walter Omar Inojosa[SUP] 12 [/SUP], Viviana Ravagnani[SUP] 13 [/SUP], Nicola Duccio Salerno[SUP] 14 [/SUP], Pier Paolo Sainaghi[SUP] 15 [/SUP], Alessandro Brignone[SUP] 16 [/SUP], Mauro Codeluppi[SUP] 17 [/SUP], Elisabetta Teopompi[SUP] 7 [/SUP], Maurizio Milesi[SUP] 18 [/SUP], Perla Bertomoro[SUP] 19 [/SUP], Norbiato Claudio[SUP] 20 [/SUP], Mario Salio[SUP] 21 [/SUP], Marco Falcone[SUP] 22 [/SUP], Giovanni Cenderello[SUP] 23 [/SUP], Lorenzo Donghi[SUP] 24 [/SUP], Valerio Del Bono[SUP] 25 [/SUP], Paolo Luigi Colombelli[SUP] 26 [/SUP], Andrea Angheben[SUP] 27 [/SUP], Angelina Passaro[SUP] 28 [/SUP], Giovanni Secondo[SUP] 29 [/SUP], Renato Pascale[SUP] 30 [/SUP], Ilaria Piazza[SUP] 31 [/SUP], Nicola Facciolongo[SUP] 32 [/SUP], Massimo Costantini[SUP] 33 [/SUP], RCT-TCZ-COVID-19 Study Group
Affiliations
- PMID: 33080005
- DOI: 10.1001/jamainternmed.2020.6615
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.