Patients hospitalized with COVID-19 pneumonia who were treated with tofacitinib (Xeljanz) had a significantly lower incidence of death or respiratory failure than those treated with placebo, a randomized trial in Brazil found.
Cumulative incidence of death or respiratory failure through day 28 was significantly lower in the tofacitinib group than in controls (18.1% vs 29.0%, respectively, RR 0.63, 95% CI 0.41-0.97), reported Otavio Berwanger, MD, PhD, of Hospital Israelita Albert Einstein in São Paulo, Brazil, and the STOP-COVID Trial Investigators.
All-cause mortality and odds of having a worse clinical outcome on the NIAID ordinal scale were both lower in the tofacitinib group, though both were non-significant, they wrote in the New England Journal of Medicine.
Berwanger and colleagues noted that the trial was not powered for these secondary outcomes, but “the direction of effects favored tofacitinib.”
NIH’s COVID-19 guidelines panel has recommended the JAK inhibitor baricitinib (Olumiant) or IL-6 inhibitor tocilizumab (Actemra) with dexamethasone or dexamethasone plus remdesivir (Veklury) for patients on high-flow oxygen or requiring non-invasive mechanical ventilation. Indeed, Berwanger’s group noted 89% of patients received glucocorticoids during hospitalization.
Tofacitinib is a selective inhibitor of JAK1 and JAK3 used to treat autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease. The drug was recently in some hot water with the FDA for a safety study that confirmed signals of increased risk of cancer and adverse cardiovascular outcomes, though the agency has yet to take definitive action.
Berwanger and colleagues theorized that because tofacitinib “modulates the action of interferons and interleukin-6, decreasing the release of cytokines,” which may cause acute respiratory distress syndrome, it might be used to treat COVID-19 patients.
“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,” they wrote.
The Study of Tofacitinib in Hospitalized Patients with Covid-19 Pneumonia (STOP-COVID) trial was a multi-center study from Sept. 16 to Dec 13, 2020. Participants were hospitalized adults with laboratory-confirmed COVID-19 and evidence of COVID-19 pneumonia on radiographic imaging who had been hospitalized less than 72 hours. They were randomized 1:1 to receive tofacitinib or placebo twice daily for up to 14 days or until hospital discharge, whichever was earlier.
Primary outcome was death or respiratory failure during 28 days of follow-up, which was defined as participants meeting the criteria for category 6-8 on the NIAID ordinal scale of disease severity.
Overall, 289 patients from 15 sites were enrolled, with 142 each receiving tofacitinib or placebo. Mean age was 56, and 65% of patients were men. About half had hypertension, and almost a quarter had diabetes mellitus.
Three-quarters of patients received supplemental oxygen at baseline, 79% were treated with glucocorticoids, though overall, 89.3% of patients received glucocorticoids over the course of the study.
Death from any cause occurred in 2.8% of the tofacitinib group and 5.5% of the placebo group (RR 0.49, 95% CI 0.15-1.63), while the odds of having a worse score on the NIAID ordinal scale were lower in the tofacitinib group at day 28 (RR 0.54, 95% CI 0.27-1.06). Median duration of hospital stay and ICU stay were similar between groups, the authors noted.
Examining safety, serious adverse events occurred in 14.1% of the tofacitinib group and 12.0% of the placebo group. Adverse events of interest included deep vein thrombosis, acute myocardial infarction, ventricular tachycardia and myocarditis in the tofacitinib group and hemorrhagic stroke and cardiogenic shock in the placebo group.
In addition, there was no difference between groups in higher risk of secondary infection or thromboembolic events, the authors noted.
“Whether the use of JAK inhibitors is superior or additive to other specific immunomodulatory therapies in patients hospitalized with Covid-19 remains to be determined,” they wrote.
This study was supported by Pfizer.
Guimarães disclosed no conflicts of interest.
Berwanger disclosed support from Pfizer, AstraZeneca, Amgen, Bayer, Servier, Boehringer-Ingelheim and Novartis.
Other co-authors disclosed employment by Pfizer, and various ties to industry.