High-Dose Dexamethasone Versus Tocilizumab in Moderate to Severe COVID-19 Pneumonia: A Randomized Controlled Trial

Abstract

Background and objectives Recent randomized controlled trials (RCTs) have indicated potential therapeutic benefits with high-dose dexamethasone (HDD) or tocilizumab (TCZ) plus standard care in moderate to severe coronavirus disease 2019 (COVID-19) with acute respiratory distress syndrome (ARDS). No study has compared these two against each other. We aimed to compare the efficacy and safety of HDD against TCZ in moderate to severe COVID-ARDS. Methods Patients admitted with moderate to severe COVID-19 ARDS with clinical worsening within 48 hours of standard care were randomly assigned to receive either HDD or TCZ plus standard care. The primary outcome was ventilator-free days (VFDs) at 28 days. The main secondary outcomes were 28-day all-cause mortality and the incidence of adverse events. Our initial plan was to perform an interim analysis of the first 42 patients. Results VFDs were significantly lower in the HDD arm (median difference: 28 days; 95% confidence interval (CI): 19.35-36.65; Cohen's d = 1.14;p < 0.001). We stopped the trial at the first interim analysis due to high 28-day mortality in the HDD arm (relative risk (RR) of death: 6.5; p = 0.007; NNT (harm) = 1.91). The incidence of secondary infections was also significantly high in the HDD arm (RR: 5.5; p = 0.015; NNT (harm) = 2.33). Conclusions In our study population, HDD was associated with a very high rate of mortality and adverse events. We would not recommend HDD to mitigate the cytokine storm in moderate to severe COVID-19 ARDS. TCZ appears to be a much better and safer alternative.

Keywords: acute respiratory distress syndrome (ards); covid-19; cytokine storms; fungal infection; high-dose dexamethasone; pulse dose steroids; secondary infection; tocilizumab.

Figure 1. Consolidated Standards of Reporting Trials (CONSORT) flow diagram of the study.

Figure 2. Outcomes. (a) Violin plot of ventilator-free days. (b) Bar diagram showing mortality distributed among the treatment group and posttreatment intubation status. One patient was intubated on the day of therapy in the tocilizumab arm and was successfully extubated as well. (c) Kaplan–Meier estimates of cumulative hospital discharge rates and (d) improvement in WHO Clinical Progression Scale.

Figure 3. Boxplots of biomarkers stratified by treatment groups and outcome (discharged/expired) at various time points: (a) PaO2/FiO2 ratio (PFR), (b) total leukocyte count (TLC), (c) neutrophil/lymphocyte ratio (N/L ratio or NLR), (d) C-reactive protein (CRP), (e) D-dimer, and (f) ferritin.

Figure 4. The proposed study protocol.

PaO₂/FiO₂: partial pressure of arterial oxygen to fraction of inspired oxygen; f/b: followed by; MPS: methylprednisolone; TLC: total leucocyte count; AST: aspartate aminotransferase; ALT: alanine aminotransferase; CRP: C-reactive protein; WHO-CPS: World Health Organization Clinical Progression Scale; NRBM: non-rebreather mask; HFNC: high-flow nasal cannula; NIV: noninvasive ventilation; IPPV: invasive positive pressure ventilation.

Figure 5. Statistical analysis/interim analysis plan.

Figure 6. Trend of PaO2/FiO2 (P/F) ratio with biomarkers in each group (median values and standard errors have been plotted).

Figure 7. Panel of violin plots showing progression over time of CRP (a and d), ferritin (b and e), and D-dimer (c and f): a, b, and c for the high-dose dexamethasone (HDD) group, and d, e, and f for the tocilizumab (TCZ) group. Pairwise comparisons are with the Wilcoxon signed-rank test.

CRP: C-reactive protein.

Figure 8. Scattergraph showing correlations between PaO2/FiO2 ratio, CRP, ferritin, and D-dimer in all cases and by groups.

HDD: high-dose dexamethasone; TCZ: tocilizumab; CRP: C-reactive protein; non-axial numbers (maroon): Spearman rank correlation coefficients; *: p-value < 0.05.

Figure 9. Competing risks regression curves for the outcome of discharge.

Figure 10. Competing risks regression curves for the outcome of death.