Tocilizumab COVID-19 Trials: Fewer Deteriorate but No Increased Survival of Severely Ill

Tocilizumab appeared to reduce likelihood of deterioration in patients with moderate COVID-19 but without improving rate of survival for the severely ill in a recent clinical trial, and the agent was considered possibly detrimental to those with severe illness in another trial published the same month.

Carlos Salama, MD, Elmhurst Hospital Center-Ichan School of Medicine at Mount Sinai Hospital, New York, NY, and colleagues reported the mixed results from their trial of tocilizumab in patients with moderate to severe COVID-19 in The New England Journal of Medicine.

A contemporaneous trial of tocilizumab in patients with severe to critical illness was prematurely stopped because of a higher mortality rate in the tocilizumab treatment group, according to the report by Viviane Veiga, MD, PhD, Brazilian Research in Intensive Care Network-BRICNet, São Paulo, Brazil and colleagues in the British Medical Journal.

Both these groups and others have investigated the anti-interleukin-6 (IL-6) receptor monoclonal antibody for patients with COVID-19 in hope that the agent, which is approved for multiple inflammatory diseases, could mitigate the dysregulated immune response and hyperinflammation associated with the acute respiratory distress and multi-organ failure marking severe stages of the illness.

"In COVID-19, an increased level of interleukin-6 and c-reactive protein (CRP) correlates with disease severity and mortality," Viega and colleagues explained. "Thus, blocking interleukin-6 activity might play a role in mitigating the inflammatory response and improve clinical outcomes inpatients with COVID-19."

Viega and colleagues sought to determine whether tocilizumab might benefit severely ill patients, selecting those with confirmed pulmonary infiltrates and receiving supplemental oxygen or requiring mechanical ventilation. Patients at 9 hospitals in Brazil were randomized 1:1 to receive either standard care and 1 dose of tocilizumab or standard care alone. Enrollment was halted at a total of 129 patients, however, when death at 15 days occurred in 11 (17%) of patients receiving tocilizumab compared with 2 (3%) in the standard care group.

"Although mortality at 15 days was not a pre-specified outcome in the trial, but rather a component of the primary outcome, a detrimental effect on this end point raised concerns about safety," Viega and colleagues indicated, "and the data monitoring committee therefore recommended early termination of the trial."

Salama and colleagues designed the EMPACTA trial (Evaluating Minority Patients with Actemra) to enroll high-risk and minority populations at sites in 6 countries. The study randomized 389 patients hospitalized for COVID-19 but not receiving mechanical ventilation at a 2:1 ratio to receive standard care in addition to 1 or 2 doses (depending on course of illness) of tocilizumab or placebo. The cohort was comprised of 56% Hispanic or Latino, 14.5% Black, 12.7% American Indian or Alaska Native, 12.7% non-Hispanic White, and 3.7% other or unknown race or ethnic group.

"Therapies for COVID-19 pneumonia are especially needed for underserved and racial and ethnic minority populations, who are disproportionately affected by the pandemic," Salama and colleagues pointed out.

In this less severely ill population, the investigators found clinical failure, as assessed in a time-to-event analysis favored tocilizumab over placebo (hazard ratio, 0.55, 95% CI 0.33 to 0.93). Death from any cause by day 28 occurred in 10.4% of patients in the tocilizumab group and 8.6% with placebo.

"Tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not improve survival," Salama and colleagues reported.

Salama and colleagues suggested that the patients most likely to benefit from tocilizumab are those with moderately severe illness, before mechanical ventilation requirement, and they posit that the agent may add to the potential benefit of treatment with antivirals and glucocorticoids.