Early administration of tocilizumab in hospitalized COVID-19 patients with elevated inflammatory markers; COVIDSTORM-a prospective, randomized, single-centre, open-label study

Abstract

Objectives: Severe COVID-19 is associated with an imbalanced immune response. We hypothesized that patients with enhanced inflammation, as demonstrated by increased levels of certain inflammatory biomarkers, would benefit from interleukin-6 blockage.

Methods: Patients hospitalized with COVID-19, hypoxemia, and at least two of four markedly elevated markers of inflammation (interleukin-6, C-reactive protein, ferritin, and/or D-dimer) were randomized for tocilizumab (TCZ) plus standard of care (SoC) or SoC alone. The primary endpoint was clinical status at day 28 assessed using a seven-category ordinal scale, and the secondary endpoints included intensive care unit admission, respiratory support, and duration of hospital admission.

Results: Clinical status at day 28 was significantly better in patients who received TCZ in addition to SoC compared with those who received SoC alone (p = 0.037). By then, 93% of patients who received TCZ (n = 53 of 57) and 86% of control patients (n = 25 of 29) had been discharged from the hospital. In addition, 47% of TCZ patients (n = 27 of 57) and 24% of control patients (n = 7 of 29) had resumed normal daily activities. The median length of hospitalization was 9 days (interquartile range, 7-12) in the TCZ group and 12 days (interquartile range, 9-15) in the control group (p = 0.014).

Discussion: In patients hospitalized with COVID-19, hypoxemia, and elevated inflammation markers, administration of TCZ in addition to SoC was associated with significantly better clinical recovery by day 28 and a shorter hospitalization compared with SoC alone.

Keywords: COVID-19; Hospitalization; Interleukin-6; SARS-CoV-2; Tocilizumab.

Fig. 1

Consolidated Standard of Reporting Trial flow chart of all screened patients. All patients admitted for COVID-19 were screened for eligibility. Excluded patients may have been excluded for several reasons. Eighty-eight patients were randomized, of whom 59 were allocated to the TCZ and 29 to the SoC group. Two patients in the TCZ group were excluded, one because of immediate withdrawal of informed consent and the other because of an ignored exclusion criterion. Data of all 57 patients who received TCZ and all 29 patients who were allocated to the SoC group were analyzed. ALT: alanine transaminase; CRP: C-reactive protein; IL-6: interleukin 6; SoC: standard of care; TCZ: tocilizumab; ULN: upper limit normal.

Fig. 2

Clinical outcome. (A and B) Clinical status of patients as assessed on a seven-category ordinal scale at randomization (day 1) and day 28. At randomization, all patients were hospitalized, and seven patients in the TCZ group (12.3%) and four patients in the SoC group (13.8%) were in the intensive care unit. On day 28, 53 patients in the TCZ group (93.0%) and 25 patients in the SoC group (86.2%) were discharged to home. On day 28, one patient in the TCZ group (1.8%) and no patients in the SoC group had died. CIs of the primary endpoint for each category in the TCZ and SoC groups are as follows: 1: 0.35–0.60, 2: 0.33–0.58, 3: 0.01–0.12, 6: 0.003–0.09, and 7: 0.003–0.09, and 1: 0.12–0.42, 2: 0.44–0.77, 4: 0.02–0.22, and 6: 0.02–0.22, respectively. CIs of hospital stays are 8 to 11 in the TCZ group and 10 to 15 in the SoC group. Categories on the ordinal scale were as follows: 1: at home, normal daily activities; 2: at home, assistance needed; 3: hospitalized, no supplemental oxygen; 4: hospitalized, receiving supplemental oxygen; 5: in ICU, no IMV or ECMO; 6: in ICU, receiving IMV; and 7: dead. ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; IMV, invasive mechanical ventilation; SoC, standard of care; TCZ, tocilizumab.

Fig. 3

C-reactive protein (CRP) in the first week after randomization. CRP values (log transformed) during the first 7 days from randomization by linear mixed models for repeated measurements. The model included group, time as categorical within factor, and group by time interaction.