The efficacy of interleukin-6 receptor blockade in hospitalized patients with coronavirus disease 2019 (Covid-19) who are not receiving mechanical ventilation is unclear.
We performed a randomized, double-blind, placebo-controlled trial involving patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hyperinflammatory states, and at least two of the following signs: fever (body temperature >38°C), pulmonary infiltrates, or the need for supplemental oxygen in order to maintain an oxygen saturation greater than 92%. Patients were randomly assigned in a 2:1 ratio to receive standard care plus a single dose of either tocilizumab (8 mg per kilogram of body weight) or placebo. The primary outcome was intubation or death, assessed in a time-to-event analysis. The secondary efficacy outcomes were clinical worsening and discontinuation of supplemental oxygen among patients who had been receiving it at baseline, both assessed in time-to-event analyses.
We enrolled 243 patients; 141 (58%) were men, and 102 (42%) were women. The median age was 59.8 years (range, 21.7 to 85.4), and 45% of the patients were Hispanic or Latino. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% confidence interval [CI], 0.38 to 1.81; P=0.64), and the hazard ratio for disease worsening was 1.11 (95% CI, 0.59 to 2.10; P=0.73). At 14 days, 18.0% of the patients in the tocilizumab group and 14.9% of the patients in the placebo group had had worsening of disease. The median time to discontinuation of supplemental oxygen was 5.0 days (95% CI, 3.8 to 7.6) in the tocilizumab group and 4.9 days (95% CI, 3.8 to 7.8) in the placebo group (P=0.69). At 14 days, 24.6% of the patients in the tocilizumab group and 21.2% of the patients in the placebo group were still receiving supplemental oxygen. Patients who received tocilizumab had fewer serious infections than patients who received placebo.
Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with Covid-19. Some benefit or harm cannot be ruled out, however, because the confidence intervals for efficacy comparisons were wide. (Funded by Genentech; ClinicalTrials.gov number, NCT04356937. opens in new tab.)
Gupta S et al.
Design: Observational, multicenter cohort study
Location: 68 hospitals in the U.S.
Patient Population: 3924 adults admitted to intensive care, of whom 433 received tocilizumab within the first 2 days after admission
Outcome: After risk adjustment, estimated 30-day mortality was 27.5% in patients who received tocilizumab and 37.1% in those who did not (risks difference, 9.6%; 95% confidence interval, 3.1%–16.0%).
Stone JH et al.
Design: Randomized, double-blind, placebo-controlled, manufacturer-funded trial
Location: 7 Boston hospitals
Patient Population: 243 adults with COVID-19 pneumonia and elevated inflammatory markers but requiring less than 10 L of oxygen per minute and not mechanically ventilated
Intervention: Randomization 2:1 to 8 mg/kg of tocilizumab or placebo
Outcome: No significant difference was seen in the need for intubation or death (hazard ratio, 0.83; 95% CI, 0.38–1.18), or disease worsening (HR, 1.11; 95% CI, 0.59–2.10).
Salvarani C et al.
Design: Open-label randomized trial
Location: 24 Italian hospitals
Patient Population: 126 adults with COVID-19 pneumonia and partial pressure of arterial oxygen to fraction of inspired oxygen between 200 and 300 mm Hg
Intervention: Participants were randomized 1:1 to 8 mg/kg of tocilizumab within 8 hours after randomization and a second dose 12 hours later, versus standard of care. Those in the standard-of-care arm were eligible for tocilizumab if progression occurred; ultimately 14 of them received tocilizumab.
Outcome: No difference in clinical worsening was seen at 14 days. The trial was stopped early due to futility.
Hermine O et al.
Design: Open-label randomized trial
Location: 9 French hospitals
Patient population: 131 patients hospitalized with COVID-19 pneumonia requiring at least 3 L of oxygen per minute but not in intensive care or mechanically ventilated
Intervention: 8 mg/kg of tocilizumab, up to 2 doses (on day 1 and day 3), versus standard of care
Outcome: No difference in mortality was seen at day 28. On day 14, the combined rate of death and noninvasive or mechanical ventilation was 24% with tocilizumab versus 36% with standard of care (HR, 0.58; 90% credible interval, 0.33–1.0).