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

被引:529
作者
Salvarani, Carlo [1 ,2 ]
Dolci, Giovanni [3 ]
Massari, Marco [4 ]
Merlo, Domenico Franco [5 ]
Cavuto, Silvio [5 ]
Savoldi, Luisa [5 ]
Bruzzi, Paolo [6 ]
Boni, Fabrizio [7 ]
Braglia, Luca [5 ]
Turra, Caterina [8 ]
Ballerini, Pier Ferruccio [9 ]
Sciascia, Roberto [9 ]
Zammarchi, Lorenzo [10 ]
Para, Ombretta [11 ]
Scotton, Pier Giorgio [12 ]
Inojosa, Walter Omar [12 ]
Ravagnani, Viviana [13 ]
Salerno, Nicola Duccio [14 ]
Sainaghi, Pier Paolo [15 ,16 ]
Brignone, Alessandro [17 ]
Codeluppi, Mauro [18 ]
Teopompi, Elisabetta [7 ]
Milesi, Maurizio [19 ]
Bertomoro, Perla [20 ]
Claudio, Norbiato [21 ]
Salio, Mario [22 ]
Falcone, Marco [23 ]
Cenderello, Giovanni [24 ]
Donghi, Lorenzo [25 ]
Del Bono, Valerio [26 ]
Colombelli, Paolo Luigi [27 ]
Angheben, Andrea [28 ]
Passaro, Angelina [29 ]
Secondo, Giovanni [30 ]
Pascale, Renato [31 ]
Piazza, Ilaria [32 ]
Facciolongo, Nicola [33 ]
Costantini, Massimo [34 ]
机构
[1] Azienda USL IRCCS Reggio Emilia, SOC Reumatol, Reggio Emilia, Italy
[2] Univ Modena & Reggio Emilia, Unita Reumatol, Reggio Emilia, Italy
[3] Univ Modena & Reggio Emilia, Unita Malattie Infett, Reggio Emilia, Italy
[4] Azienda USL IRCCS Reggio Emilia, SOC Malattie Infett, Reggio Emilia, Italy
[5] Azienda USL IRCCS Reggio Emilia, SC Infrastruttura Ric & Stat, Reggio Emilia, Italy
[6] IRCCS Osped Policlin San Martino, SC Epidemiol Clin, Genoa, Italy
[7] Azienda USL IRCCS Reggio Emilia, SOC Internist Multidisciplinare, Reggio Emilia, Italy
[8] Azienda USL IRCCS Reggio Emilia, SOC Farm, Reggio Emilia, Italy
[9] UOC Med Gen Osped Vittorio Veneto, Treviso, Italy
[10] Univ Firenze, AOU Careggi, SOD Malattie Infett & Trop, Dipartimento Med Sperimentale & Clin, Florence, Italy
[11] AOU Careggi, Dipartimento Emergenza Accettaz, Med Interna 1, Florence, Italy
[12] Osped Reg Ca Foncello Treviso, UO Malattie Infett, Treviso, Italy
[13] ASST Mantova, SSD Ctr DH Allergol & Immunol Clin, Mantva, Italy
[14] AOUI Verona, UOC Malattie Infett & Trop, Verona, Italy
[15] Univ Piemonte Orientale, DIMET, SS Reumatol, SC Med Interna, Vercelli, Italy
[16] AOU Maggiore Carita Novara, Novara, Italy
[17] Osped S Andrea, Reumatol Med Interna, La Spezia, Italy
[18] AUSL Piacenza, UOC Malattie Infett, Piacenza, Italy
[19] ASST Cremona, Unita Malattie Infett, Cremona, Italy
[20] ULSS6 Euganea Osped Riuniti Padova Sud, UOC Med Generale, Padua, Italy
[21] AO Ordine Mauriziano, SC Med Interna, Turin, Italy
[22] AO SS Antonio & Biagio & C Arrigo, SC Malattie Apparato Resp, Alessandria, Italy
[23] Univ Pisa, Unita Malattie Infett, Dipartimento Med Clin & Sperimentale, Pisa, Italy
[24] ASL1 Imperia, Malattie Infett, Imperia, Italy
[25] AOU Parma, UO Malattie Infett & Epatol, Parma, Italy
[26] AOS Croce & Carle, Malattie Infett & Trop, Cuneo, Italy
[27] ASST Bergamo Ovest, Osped Treviglio, UO Med, Bergamo, Italy
[28] IRCCS Osped Sacro Cuore Don Calabria, Dipartimento Malattie Infett Trop & Microbiol, Verona, Italy
[29] Med Interna Univ, AOU Ferrara, Ferrara, Italy
[30] Osped Evangelico, Med Interna, Genoa, Italy
[31] Univ Bologna, UO Malattie Infett, Dipartimento Sci Med & Chirurg, Bologna, Italy
[32] AUSSS3 Serenissima, UOC Med Interna, Venice, Italy
[33] Azienda USL IRCCS Reggio Emilia, SOC Pneumol, Reggio Emilia, Italy
[34] Azienda USL IRCCS Reggio Emilia, Reggio Emilia, Italy
关键词
D O I
10.1001/jamainternmed.2020.6615
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 (Pao(2)/Fio(2)) 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 Pao(2)/Fio(2) 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 Pao(2)/Fio(2) 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.
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收藏
页码:24 / 31
页数:8
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