Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial.

OBJECTIVE: To determine whether tocilizumab improves clinical outcomes for patients with severe or critical coronavirus disease 2019 (covid-19). DESIGN: Randomised, open label trial. SETTING: Nine hospitals in Brazil, 8 May to 17 July 2020. PARTICIPANTS: Adults with confirmed covid-19 who were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two serum biomarkers (C reactive protein, D dimer, lactate dehydrogenase, or ferritin). The data monitoring committee recommended stopping the trial early, after 129 patients had been enrolled, because of an increased number of deaths at 15 days in the tocilizumab group. INTERVENTIONS: Tocilizumab (single intravenous infusion of 8 mg/kg) plus standard care (n=65) versus standard care alone (n=64). MAIN OUTCOME MEASURE: The primary outcome, clinical status measured at 15 days using a seven level ordinal scale, was analysed as a composite of death or mechanical ventilation because the assumption of odds proportionality was not met. RESULTS: A total of 129 patients were enrolled (mean age 57 (SD 14) years; 68% men) and all completed follow-up. All patients in the tocilizumab group and two in the standard care group received tocilizumab. 18 of 65 (28%) patients in the tocilizumab group and 13 of 64 (20%) in the standard care group were receiving mechanical ventilation or died at day 15 (odds ratio 1.54, 95% confidence interval 0.66 to 3.66; P=0.32). Death at 15 days occurred in 11 (17%) patients in the tocilizumab group compared with 2 (3%) in the standard care group (odds ratio 6.42, 95% confidence interval 1.59 to 43.2). Adverse events were reported in 29 of 67 (43%) patients who received tocilizumab and 21 of 62 (34%) who did not receive tocilizumab. CONCLUSIONS: In patients with severe or critical covid-19, tocilizumab plus standard care was not superior to standard care alone in improving clinical outcomes at 15 days, and it might increase mortality. TRIAL REGISTRATION: ClinicalTrials.gov NCT04403685.

Study protocol for the Balanced Solution versus Saline in Intensive Care Study (BaSICS): a factorial randomised trial.

BACKGROUND: The effectiveness and safety of balanced crystalloid fluids compared with saline (0.9% sodium chloride) as a fluid of choice in critically ill patients remain unclear. The effects of different fluid infusion rates on outcomes are also unknown. OBJECTIVES: To test the hypothesis that a balanced crystalloid solution, compared with saline, decreases 90-day all-cause mortality among critically ill patients; and to test the hypothesis that slow, compared with rapid, infusion rate decreases 90-day mortality in this population of patients. METHODS: The Balanced Solution versus Saline in Intensive Care Study (BaSICS) is a pragmatic, 2 ??2 factorial, randomised controlled trial. A total of 11 000 patients will be recruited from at least 100 Brazilian intensive care units. Patients will be randomised to receive Plasma-Lyte 148 or saline, and to rapid infusion (999 mL/h) or slow infusion (333 mL/h). Study fluids will be used for resuscitation episodes (at rapid or slow infusion rates), dilution of compatible medications and maintenance solutions. Patients, health care providers and investigators will be blinded to the solutions being tested. The rate of bolus infusion will not be blinded. OUTCOMES: The primary outcome is 90-day all-cause mortality. Secondary outcomes are: incidence of renal failure requiring renal replacement therapy within 90 days, incidence of acute kidney injury (Kidney Disease: Improving Global Outcomes stages 2 and 3), incidence of non-renal organ dysfunction assessed by Sepsis-related Organ Failure Assessment score at Days 3 and 7, and number of mechanical ventilationfree days within the first 28 days after randomisation. RESULTS AND CONCLUSIONS: The BaSICS trial will provide robust evidence on whether a balanced crystalloid, compared with saline, improves important patient outcomes in critically ill patients. BaSICS will also provide relevant information on whether bolus infusion rate affects outcomes in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02875873.