Randomized Phase 3 Trial of Ruxolitinib for COVID-19–Associated Acute Respiratory Distress Syndrome*

Abstract

OBJECTIVES: Evaluate the safety and efficacy of the Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib in COVID-19–associated acute respiratory distress syndrome requiring mechanical ventilation. DESIGN: Phase 3 randomized, double-blind, placebo-controlled trial Ruxolitinib in Participants With COVID-19–Associated Acute Respiratory Distress Syndrome Who Require Mechanical Ventilation (RUXCOVID-DEVENT; NCT04377620). SETTING: Hospitals and community-based private or group practices in the United States (29 sites) and Russia (4 sites). PATIENTS: Eligible patients were greater than or equal to 12 years old, hospitalized with severe acute respiratory syndrome coronavirus 2 infection, and mechanically ventilated with a Pa o 2 /F io 2 of less than or equal to 300 mm Hg within 6 hours of randomization. INTERVENTIONS: Patients were randomized 2:2:1 to receive twice-daily ruxolitinib 15 mg, ruxolitinib 5 mg, or placebo, each plus standard therapy. MEASUREMENTS AND MAIN RESULTS: The primary endpoint, 28-day mortality, was tested for each ruxolitinib group versus placebo using a mixed-effects logistic regression model and one-tailed significance test (significance threshold: p < 0.025); no type 1 error was allocated to secondary endpoints. Between May 24, 2020 and December 15, 2020, 211 patients (age range, 24–87 yr) were randomized (ruxolitinib 15/5 mg, n = 77/87; placebo, n = 47). Acute respiratory distress syndrome was categorized as severe in 27% of patients (58/211) at randomization; 90% (190/211) received concomitant steroids. Day-28 mortality was 51% (39/77; 95% CI, 39–62%) for ruxolitinib 15 mg, 53% (45/85; 95% CI, 42–64%) for ruxolitinib 5 mg, and 70% (33/47; 95% CI, 55–83%) for placebo. Neither ruxolitinib 15 mg (odds ratio, 0.46 [95% CI, 0.201–1.028]; one-sided p = 0.029) nor 5 mg (odds ratio, 0.42 [95% CI, 0.171–1.023]; one-sided p = 0.028) significantly reduced 28-day mortality versus placebo. Numerical improvements with ruxolitinib 15 mg versus placebo were observed in secondary outcomes including ventilator-, ICU-, and vasopressor-free days. Rates of overall and serious treatment-emergent adverse events were similar across treatments. CONCLUSIONS: The observed reduction in 28-day mortality rate between ruxolitinib and placebo in mechanically ventilated patients with COVID-19–associated acute respiratory distress syndrome was not statistically significant; however, the trial was underpowered owing to early termination.

Therapeutic implications of current Janus kinase inhibitors as anti-COVID agents: A review

“…Currently, there are 22 clinical studies listed on ClinicalTrials.gov , only six studies have been completed, and an equal number of trials have been terminated or withdrawn ( Table 2 ). Notably, sponsors terminated an interventional phase III clinical trial (RUXCOVID-DEVENT), observing no significant difference in the 28-day mortality rate in ruxolitinib group and placebo group in the ruxolitinib group and placebo group COVID-19-associated acute respiratory distress syndrome patients on mechanical ventilation ( Rein et al, 2022 ). Similarly, in another international, randomized, phase 3 trial (RUXCOVID; NCT04362137) of ruxolitinib vs. placebo, associated with the standard of care in hospitalized COVID-19 patients but not on mechanical ventilation or in ICU, ruxolitinib 5 mg BID did not meet its primary endpoint and demonstrated no benefit in the overall studied population ( Han et al, 2022 ).…”

Recognition of Differentially Expressed Molecular Signatures and Pathways Associated with COVID-19 Poor Prognosis in Glioblastoma Patients

“…In light of the current study, we can therefore consider methotrexate a reasonable option [ 45 ]. Ruxolitinib, the third most-screened medicine, is known for inhibiting JAK1 and JAK2 and thereby inhibiting tumor invasion and tumorigenesis in human GBM, and it was also employed during COVID-19 for combined antiviral and anti-inflammatory therapy [ 46 , 47 ]. As a result, these medications already demonstrated their efficacy during the pandemic in patients who were already suffering from various ailments.…”

Randomized phase II clinical trial of ruxolitinib plus simvastatin in COVID19 clinical outcome and cytokine evolution

“…In this setting, dexamethasone has demonstrated an impact on overall mortality in a randomized phase III clinical trial and has been adopted as standard of care (9). On the other hand, tocilizumab, an interleukin-6 receptor antagonist, reached more conflicting results and is commonly administered to patients that do not respond to initial therapies (10,25).…”

“…The RUXCOVID-DEVENT trial compared the activity of two doses of ruxolitinib (5 mg or 15mg twice a day) versus placebo in more than 200 cases hospitalized with severe acute respiratory syndrome due coronavirus 2 ( 26 ). However, no significant difference in mortality was observed.…”