No abstract

Background No therapy is approved for COVID-19 pneumonia. The aim of this study was to assess the role of tocilizumab in reducing the risk of invasive mechanical ventilation and death in patients with severe COVID-19 pneumonia who received standard of care treatment.Methods This retrospective, observational cohort study included adults (≥18 years) with severe COVID-19 pneumonia who were admitted to tertiary care centres in Bologna and Reggio Emilia, Italy, between Feb 21 and March 24, 2020, and a tertiary care centre in Modena, Italy, between Feb 21 and April 30, 2020. All patients were treated with the standard of care (ie, supplemental oxygen, hydroxychloroquine, azithromycin, antiretrovirals, and low molecular weight heparin), and a non-randomly selected subset of patients also received tocilizumab. Tocilizumab was given either intravenously at 8 mg/kg bodyweight (up to a maximum of 800 mg) in two infusions, 12 h apart, or subcutaneously at 162 mg administered in two simultaneous doses, one in each thigh (ie, 324 mg in total), when the intravenous formulation was unavailable. The primary endpoint was a composite of invasive mechanical ventilation or death. Treatment groups were compared using Kaplan-Meier curves and Cox regression analysis after adjusting for sex, age, recruiting centre, duration of symptoms, and baseline Sequential Organ Failure Assessment (SOFA) score. FindingsOf 1351 patients admitted, 544 (40%) had severe COVID-19 pneumonia and were included in the study. 57 (16%) of 365 patients in the standard care group needed mechanical ventilation, compared with 33 (18%) of 179 patients treated with tocilizumab (p=0•41; 16 [18%] of 88 patients treated intravenously and 17 [19%] of 91 patients treated subcutaneously). 73 (20%) patients in the standard care group died, compared with 13 (7%; p<0•0001) patients treated with tocilizumab (six [7%] treated intravenously and seven [8%] treated subcutaneously). After adjustment for sex, age, recruiting centre, duration of symptoms, and SOFA score, tocilizumab treatment was associated with a reduced risk of invasive mechanical ventilation or death (adjusted hazard ratio 0•61, 95% CI 0•40-0•92; p=0•020). 24 (13%) of 179 patients treated with tocilizumab were diagnosed with new infections, versus 14 (4%) of 365 patients treated with standard of care alone (p<0•0001).Interpretation Treatment with tocilizumab, whether administered intravenously or subcutaneously, might reduce the risk of invasive mechanical ventilation or death in patients with severe COVID-19 pneumonia.

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.