Interventional study with open label/non-randomised methodology (Yellow)
The objective of this prospective, open-label, randomised clinical trial recently published in JAMA Internal Medicine, was to evaluate the effect of early tocilizumab administration vs standard therapy in preventing clinical worsening in patients hospitalised with COVID-19 pneumonia. Hospitalised patients with COVID-19 pneumonia were randomised between March 31 and June 11, 2020, 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 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. Patients in the experimental arm received intravenous tocilizumab within 8 hours from randomisation (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. 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. A total of 126 patients were randomised (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 randomisation (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 randomisation, and 6 and 5 patients were intubated in the 2 groups, respectively.
The trial was prematurely interrupted after an interim analysis for futility. In this randomised clinical trial of hospitalised 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. The authors underlined that further blinded, placebo-controlled randomised clinical trials are needed to confirm the results and to evaluate possible applications of tocilizumab in different stages of the disease.