Safety and Efficacy of Tocilizumab 4 or 8 mg/kg in Hospitalized Patients With Moderate to Severe Coronavirus Disease 2019 Pneumonia: A Randomized Clinical Trial

Abstract

Background: Tocilizumab, an interleukin 6 receptor (IL-6R) antagonist monoclonal antibody, has shown efficacy in patients with coronavirus disease 2019 (COVID-19) pneumonia, but the optimal dose is unknown.

Methods: Patients hospitalized for moderate to severe COVID-19 pneumonia were randomized 1:1 to receive standard of care treatment and 1-2 doses of intravenous tocilizumab 4 mg/kg or 8 mg/kg (open-label). Primary pharmacokinetic and pharmacodynamic end points were serum concentrations of tocilizumab and soluble interleukin 6 receptor (sIL-6R), IL-6, ferritin, and C-reactive protein (CRP), from baseline to day 60. The secondary end point was safety. Key exploratory efficacy end points included clinical status, time to discharge, mortality rate, and incidence of mechanical ventilation.

Results: Of 100 patients randomized, 49 received tocilizumab 4 mg/kg and 48 received 8 mg/kg. In pharmacokinetic and sIL-6R assessments, dose-dependent differences were seen in patients who received 1 or 2 doses of 4 or 8 mg/kg. Serum concentrations of IL-6, ferritin, and CRP and safety outcomes were comparable between groups. Through day 60, serious adverse events were reported in 30.6% and 25.0% of patients in the 4- and 8-mg/kg groups, respectively. Eight patients (16.3%) in the 4-mg/kg group and 6 (12.5%) in the 8-mg/kg group died. Exploratory time-to-event outcomes favored 8 mg/kg within the first 2 weeks.

Conclusions: In patients with moderate to severe COVID-19 pneumonia who received tocilizumab 4 or 8 mg/kg, pharmacokinetic and sIL-6R assessments showed expected dose-dependent effects; pharmacodynamic assessments and safety were comparable, with no new safety signals. Further study is required before a lower dose of tocilizumab can be recommended in patients with COVID-19 pneumonia.

Clinical trials registration: NCT04363736.

Keywords: COVID-19; pharmacodynamics; pharmacokinetics; safety; tocilizumab.

Figure 1.

Study flowchart. Abbreviations: mITT, modified intention-to-treat; PK, pharmacokinetic.

Figure 2.

Serum tocilizumab concentration over time by 4-mg/kg (1 or 2 doses) vs 8-mg/kg (1 or 2 doses) groups in the pharmacokinetic population. Data points around the nominal time of 1 and 2 days included pre– and post–second infusion measurements for patients receiving a second infusion. Values below the limit of quantitation were set to 0 prior to maximum concentration and missing thereafter. Abbreviations: SOC, standard of care; TCZ, tocilizumab.

Figure 3.

Pharmacodynamics of soluble interleukin 6 receptor (A), interleukin 6 (B), C-reactive protein (C), and ferritin (D) in the modified intention-to-treat population. C-reactive protein and ferritin levels presented were from a central laboratory (QPS Netherlands). Values below the limit of quantitation were set to 0 predose and 0.5 times the lower limit of quantitation thereafter. Day 21 samples for 1 patient were collected on actual day 27. Day 60 was assumed as any study completion visit after day 50. Abbreviations: SOC, standard of care; TCZ, tocilizumab.