Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia

Abstract

Background The efficacy and safety of tofacitinib, a Janus kinase inhibitor, in patients who are hospitalized with coronavirus disease 2019 (Covid-19) pneumonia are unclear. Methods We randomly assigned, in a 1:1 ratio, hospitalized adults with Covid-19 pneumonia to receive either tofacitinib at a dose of 10 mg or placebo twice daily for up to 14 days or until hospital discharge. The primary outcome was the occurrence of death or respiratory failure through day 28 as assessed with the use of an eight-level ordinal scale (with scores ranging from 1 to 8 and higher scores indicating a worse condition). All-cause mortality and safety were also assessed. Results A total of 289 patients underwent randomization at 15 sites in Brazil. Overall, 89.3% of the patients received glucocorticoids during hospitalization. The cumulative incidence of death or respiratory failure through day 28 was 18.1% in the tofacitinib group and 29.0% in the placebo group (risk ratio, 0.63; 95% confidence interval [CI], 0.41 to 0.97; P=0.04). Death from any cause through day 28 occurred in 2.8% of the patients in the tofacitinib group and in 5.5% of those in the placebo group (hazard ratio, 0.49; 95% CI, 0.15 to 1.63). The proportional odds of having a worse score on the eight-level ordinal scale with tofacitinib, as compared with placebo, was 0.60 (95% CI, 0.36 to 1.00) at day 14 and 0.54 (95% CI, 0.27 to 1.06) at day 28. Serious adverse events occurred in 20 patients (14.1%) in the tofacitinib group and in 17 (12.0%) in the placebo group. Conclusions Among patients hospitalized with Covid-19 pneumonia, tofacitinib led to a lower risk of death or respiratory failure through day 28 than placebo. (Funded by Pfizer; STOP-COVID ClinicalTrials.gov number, NCT04469114 .)

Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial

“…The JAK inhibitors ruxolitinib and tofacitinib have also been associated with reductions in mortality in small, single-country, multicentre, randomised controlled trials. 31 , 32 To our knowledge, baricitinib showed the largest effect size on mortality of any COVID-19 treatment reported in other randomised trials in hospitalised patients, and showed a benefit in addition to the use of standard of care (corticosteroids) alone. 5 , 6 , 7 , 8 …”

The Binary Model of Chronic Diseases Applied to COVID-19

“…A recent placebo controlled study in 289 COVID-19 Brazilian patients hospitalized with pneumonia, have shown that "tofacitinib led to a lower risk of death or respiratory failure through day 28 than placebo" (74).…”

Response to: Correspondence on “Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis” by van Vollenhovenet al

“…This, they posit, may explain why we found JAKi to be associated with worse outcomes while randomised controlled trials (RCTs) have found JAKi to be effective for improving outcomes when used to treat severe COVID-19. [4][5][6] In contrast to other biologic/ targeted synthetic disease-modifying antirheumatic drugs (b/ tsDMARDs) (eg, tumor necrosis factor inhibitors, abatacept), JAKi have a short half-life so discontinuation with the onset of infection may mean that patients who progress to the hyperinflammatory phase of illness, around 7-10 days after acute SARS-CoV-2 infection, are no longer experiencing the potential beneficial effects of JAKi on their immune response.…”

“…The vast majority of patients included in RCTs evaluating the efficacy of JAKi for COVID-19 have had severe infection requiring at least supplemental oxygen and were presumably experiencing the hyperinflammatory phase of the SARS-CoV-2 infection. [4][5][6] No clinical trial data are available regarding use of JAKi in outpatients with COVID-19, and current treatment paradigms include only antiviral strategies such as monoclonal antibodies to reduce disease progression in outpatients with COVID-19. 7 Whether early use of targeted immunosuppression in select outpatients with COVID-19 has a role in reducing disease progression remains to be determined.…”