Tofacitinib lowers risks for death, respiratory failure in COVID-19 pneumonia
Treatment with tofacitinib led to a lower risk for death or respiratory failure through day 28, compared with placebo, in patients hospitalized with COVID-19 pneumonia, according to data published in The New England Journal of Medicine.
“Severe manifestations of SARS-CoV-2 infection are associated with an exaggerated immune response driven by interleukin-6, tumor necrosis factor , and other cytokines in a pattern called a cytokine storm,” Patrícia O. Guimarães, MD, PhD, of the Hospital Israelita Albert Einstein, in São Paulo, Brazil, and colleagues wrote. “Tofacitinib is an orally administered selective inhibitor of Janus kinase (JAK) 1 and JAK3, with functional selectivity for JAK2, that blocks intracellular transduction pathways after a cytokine is bound to its receptor.”
“As a consequence, no cellular response is triggered, and cytokine production is indirectly suppressed,” they added. “Tofacitinib also modulates the action of interferons and interleukin-6, decreasing the release of cytokines by type 1 and type 17 helper T cells, which are implicated in the pathogenesis of the acute respiratory distress syndrome. Thus, the action of tofacitinib on multiple critical pathways of the inflammatory cascade may ameliorate progressive, inflammation-driven lung injury in hospitalized patients with COVID-19.”
To examine the efficacy and safety of tofacitinib (Xeljanz, Pfizer) in patients who are hospitalized with COVID-19 pneumonia, Guimarães and colleagues conducted the Study of Tofacitinib in Hospitalized Patients with COVID-19 Pneumonia (STOP-COVID), a multicenter, randomized, double-blind, placebo-controlled trial. A total of 289 hospitalized adults from 15 sites in Brazil were randomized 1:1 to receive 10 mg of tofacitinib twice daily or a placebo for up to 14 days or until they were discharged. In all, 89.3% of the participants received glucocorticoids during hospitalization.
The primary outcome was the occurrence of death or respiratory failure through day 28. The researchers assessed outcomes using an eight-level ordinal scale, with scores ranging from one to eight. Higher scores indicated a worse condition. The researchers also examined all-cause mortality and safety.
According to the researchers, the cumulative incidence of death or respiratory failure through day 28 was 18.1% in the tofacitinib group, compared with 29% among those who received a placebo (RR = 0.63; 95% CI, 0.41-0.97). Meanwhile, any-cause death through day 28 occurred in 2.8% of the patients in the tofacitinib group, compared with 5.5% of those in the placebo group (HR = 0.49; 95% CI, 0.15-1.63).
The researchers additionally found that the proportional odds of demonstrating a worse score on the eight-level ordinal scale with tofacitinib, compared with a placebo, was 0.6 (95% CI, 0.36-1) at day 14, and 0.54 (95% CI, 0.27-1.06) at day 28.
Regarding safety, serious adverse events occurred in 14.1% of participants in the tofacitinib group, compared with 12% of those who received a placebo.
“In this randomized, double-blind, placebo-controlled trial involving hospitalized patients with COVID-19 pneumonia, tofacitinib was superior to placebo in reducing the incidence of death or respiratory failure through day 28,” Guimarães and colleagues wrote. “These effects were consistent regardless of sex, age, duration of symptoms, and use of glucocorticoids at baseline; they were also consistent across different levels of supplemental oxygen use at baseline.”
“Although STOP-COVID was not powered to detect a difference in mortality or in the incidence of other secondary outcomes between the two groups, the direction of effects favored tofacitinib,” they added. “Finally, tofacitinib was not associated with a higher risk of secondary infection or thromboembolic events.”