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

Lindsay Rein, MD; Karel Calero, MD; Ronak Shah, MD; Charles Ojielo, MD; Kristin M. Hudock, MD, MSTR; Saba Lodhi, MD; Farid Sadaka, MD; Shashi Bellam, MD; Christopher Palma, MD, ScM; David N. Hager, MD, PhD; Jeannie Daniel, PhD; Richard Schaub, MS; Kevin O'Hayer, MD, PhD; Nicole M. Theodoropoulos, MD, MS


Crit Care Med. 2022;50(12):1701-1713. 

In This Article

Abstract and Introduction


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 PaO 2/FIO 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.


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global health emergency, with many people developing clinically significant COVID-19, and 20% requiring hospitalization.[1–3] One third of hospitalized patients develop acute respiratory distress syndrome (ARDS), a life-threatening inflammatory lung condition characterized by loss of aerated tissue, severe hypoxemia, and increased dead space.[4,5] Despite standard use of lung-protective ventilation strategies and prone positioning, patients with COVID-19–associated ARDS requiring invasive mechanical ventilation have poor outcomes.[4,6–8] Among these patients, only dexamethasone plus interleukin (IL)-6 inhibition or Janus kinase (JAK) inhibition has been shown to improve survival, but mortality remains high.[9–11] Therefore, an unmet need remains for additional effective therapies.

COVID-19 is associated with aberrant cytokine signaling, including overactivation of the JAK/signal transducers and activators of transcription (STAT) pathway.[12] Several cytokines that activate JAK/STAT signaling, including interferon-γ, granulocyte-macrophage colony-stimulating factor, IL-2, and IL-6, are overexpressed in patients with COVID-19,[13,14] and inhibiting some of these inflammatory mediators is associated with clinical improvement compared with standard of care.[10,15,16] The IL-6 inhibitor tocilizumab has received emergency use authorization; however, evidence from randomized trials of patients with severe disease is mixed.[10,17] Because the COVID-19–associated cytokine storm involves several cytokines in addition to IL-6, blocking multiple inflammatory mediators via JAK/STAT inhibition is a rational therapeutic approach.[12] Furthermore, the inflammatory response of COVID-19 exhibits a similar macrophage-derived cytokine profile as hemophagocytic lymphohistiocytosis,[18] which is responsive to the selective JAK1/JAK2 inhibitor ruxolitinib.[19,20] Several reports have provided proof of concept for JAK inhibition for the treatment of critically ill patients with COVID-19;[11,21–24] however, only one exploratory study has investigated a JAK inhibitor (baricitinib) specifically in patients with COVID-19–associated ARDS requiring mechanical ventilation.[11] The objective of this study was to evaluate the effects on mortality and in-hospital outcomes (ventilator-, ICU-, oxygen-, vasopressor-, and hospital-free days) as well as the safety of the investigational agent ruxolitinib in mechanically ventilated patients with COVID-19–associated ARDS.