On the heels of several trials failing to demonstrate efficacy of tocilizumab for COVID-19 infection, the Evaluating Minority Patients with Actemra (EMPACTA) trial provides evidence that tocilizumab may reduce progression to mechanical ventilation but not short-term mortality in patients hospitalized with COVID-19 pneumonia. Tocilizumab is a monoclonal antibody directed against the interleukin-6 (IL-6) receptor. IL-6, a pro-inflammatory cytokine, is often elevated in patients with severe COVID-19 and is thought to play a pivotal role in precipitating the inflammatory response that drives acute respiratory distress syndrome (ARDS). Antagonism of IL-6 receptors by tocilizumab results in a decrease in IL-6, other cytokines, and acute phase reactants. Tocilizumab is increasingly being prescribed off-label for patients with COVID-19, although evidence for its use has been limited.
EMPACTA trial investigators randomized 388 adults (59% men, mean age 56, 2:1 ratio drug:placebo) hospitalized with COVID-19 and oxygen saturation less than 94 percent to one or two doses of tocilizumab eight mg/kg IV or saline infusion. Patients in the tocilizumab arm received a second dose if clinical symptoms worsened or if they failed to improve. All patients received standard of care, which could include antiviral treatment or systemic glucocorticoids. The primary efficacy outcome was a composite of mechanical ventilation or death at 28 days. This phase 3 clinical trial emphasized inclusion of underserved patient populations from the United States, Mexico, Kenya, South Africa, Peru, and Brazil. Consequently, more than 80 percent of participants were Hispanic or Latino, Black, American Indian, or Alaska Native.
A modified intention-to-treat analysis of 377 patients who completed the trial found that there was no significant difference in 28-day mortality (10.4% with tocilizumab vs. 8.6% with placebo). However, the percentage of patients who received mechanical ventilation or who had died by day 28 was lower in the tocilizumab group than in the placebo group (12% vs.19.3%, p = 0.04, NNT 14). Results were similar when stratified by age, race or ethnic group, geographic region, glucocorticoid use, antiviral use, and the number of doses of tocilizumab or placebo received.
It should be noted that this trial was funded by Genentech, which manufactures tocilizumab, designed and conducted the trial, and also performed analysis of its results. Despite the potential for bias, the fact that this trial showed no mortality benefit with tocilizumab is consistent with prior randomized trials evaluating tocilizumab for COVID-19. The Boston Area COVID-19 Consortium (BACC) Bay Tocilizumab trial, in contrast, did not find tocilizumab effective for preventing progression to intubation. Participants in that trial were sicker overall, and although some were treated with remdesivir, none received dexamethasone. It’s possible that the effect size of tocilizumab may be greater in patients receiving dexamethasone, which we now consider standard of care. Although tocilizumab is costly, it seems to be a relatively safe medication with some potential to ease the burden on critical care resources. This study provides intriguing evidence that may help refine the role of tocilizumab in COVID-19 infections. Of note, the UK recently approved tocilizumab after preliminary results of the not-yet-peer-reviewed Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) demonstrated improved survival in patients with COVID-19 in the ICU.
For more information, see the topic COVID-19 (Novel Coronavirus) in DynaMed.
