Treatment with the Janus kinase (JAK) inhibitor tofacitinib was associated with a lower risk for death or respiratory failure compared with placebo among patients hospitalized with pneumonia related to Covid-19 who were not on mechanical ventilation, according to results from the multicenter, randomized Study of Tofacitinib in Hospitalized Patients with Covid-19 (STOP-COVID) clinical trial conducted in Brazil.
Results showed a benefit for JAK inhibition in a population in which most patients were also receiving glucocorticoid therapy. The cumulative incidence of death or respiratory failure through day 28 was roughly 18% in the patients randomized to the tofacitinib arm of the study, compared with 29% in the placebo group.
Researcher Otavio Berwanger, MD, PhD, of San Paulo, Brazil’s Hospital Israelita Albert Einstein, and fellow STOP-COVID Trial investigators wrote that results from their trial and the recently reported ACTT-2 study of baricitinib plus remdesivir “provide evidence that JAK inhibition represents an additional therapeutic option for treating Covid-19 pneumonia in patients who are not on invasive mechanical ventilation.
Findings from the STOP-COVID trial were published online June 16 in The New England Journal of Medicine.
They noted that the severest form of Covid-19 often involves what is now referred to as ’cytokine storm,’ involving exaggerated immune response driven by interleukin-6, tumor necrosis factor α, and other cytokines. Tofacitinib and related drugs indirectly suppress cytokine production “by selectively inhibiting Janus kinase (JAK) 1 and JAK3, with functional selectivity for JAK2, that blocks intracellular transduction pathways after a cytokine is bound to its receptor,” Berwanger and colleagues wrote.
They conducted their double-blind clinical trial to examine the efficacy and safety of tofacitinib in hospitalized patients with Covid-19 who did not require non-invasive or invasive ventilation at enrollment. Patients were randomized 1:1 to treatment with oral tofacitinib (10 mg twice daily until hospital discharge or up to 14 days) (n=144) or placebo (n=145). The primary study outcome was death or respiratory failure through day 28, assessed using an eight-level ordinal scale, with scores ranging from 1 to 8. Higher scores indicated a worse condition.
A total of 289 patients were randomized at 15 sites in Brazil from mid-September through mid-December, 2020, with roughly 9-out-of-10 (89.3%) receiving glucocorticoids during hospitalization. Twenty patients in each group were also being concomitantly treated with the antiviral oseltamivir.
Patient baseline characteristics were similar in the two groups, and the mean patient age was 56 years. Just over a third (34.9%) of patients were women, median time from symptom onset to randomization was 10 days, and median time from the diagnosis of Covid-19 to randomization was 5 days.
Among the main findings:
- Death or respiratory failure through day 28 occurred in 18.1% of the patients in the tofacitinib group and in 29.0% of those in the placebo group (risk ratio, 0.63; 95% CI, 0.41-0.97; P=0.04).
- Results from sensitivity analyses for the primary outcome, including the analysis that was adjusted for use of glucocorticoids, were similar to those of the main analysis.
- The results were also consistent regardless of patient baseline scores on the ordinal scale, and primary outcome results were generally consistent across prespecified subgroups.
- Death from any cause through day 28 occurred in 2.8% of patients in the tofacitinib group and in 5.5% of those in the placebo group (hazard ratio, 0.49; 95% CI, 0.15-1.63).
- The median duration of hospital stay and ICU stay were similar in the two groups.
Serious adverse events occurred in 14.1% of patients in the tofacitinib group and 12.0% of patients in the placebo group.
Berwanger et al noted that the findings expand on the earlier data from the ACTT-2 trial, which largely included patients who were not receiving glucocorticoids.
Glucocorticoid therapy has been demonstrated to reduce mortality among patients hospitalized with Covid-19 receiving oxygen therapy. In a meta-analysis of seven randomized trials, corticosteroid therapy was associated with lower mortality among critically ill patients who were and were not receiving invasive mechanical ventilation at randomization.
“On the basis of these results, glucocorticoids are recommended by current guidelines as part of the standard care for this patient population. Our findings show that tofacitinib, when added to standard care including glucocorticoids, led to a lower risk or clinical events among patients hospitalized with Covid-19 pneumonia than placebo,” Berwanger and colleagues wrote.
They were unable to assess the impact of the addition of tofacitinib to treatment with remdesivir, given that remdesivir was not available for use in Brazil during the trial.
Several other specific immune modulators are under investigation for the treatment of Covid-19 pneumonia, including anticytokines such as interleukin-1 and interleukin-6 receptor antagonists (anakinra, tocilizumab, sarilumab, and siltuximab), tumor necrosis factor inhibitors (adalimumab and infliximab), and granulocyte–macrophage colony-stimulating factors (gimsilumab, lenzilumab, and namilumab).
“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,” concluded Berwanger and colleagues.
Among patients hospitalized with pneumonia related to Covid-19 who were not on mechanical ventilation, treatment with the Janus kinase inhibitor tofacitinib was associated with a lower risk for death or respiratory failure compared to placebo.
The cumulative incidence of death or respiratory failure through day 28 was roughly 18% in the patients randomized to the tofacitinib arm of the STOP-COVID study, compared with 29% in the placebo group.
Salynn Boyles, Contributing Writer, BreakingMED™
This research was funded by Pfizer.
Berwanger reported reports receiving grants from Pfizer, during the conduct of the study; grants from AstraZeneca, grants from Amgen, grants from Bayer, grants from Servier, grants from Boehringer-Ingelheim, grants from Novartis, outside the submitted work.
Cat ID: 190
Topic ID: 79,190,254,930,500,501,502,521,728,791,932,730,933,190,926,192,927,195,929,925,934