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

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 o2 /F io2 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.

Family automated voice reorientation (FAVoR) intervention for mechanically ventilated patients in the intensive care unit: Study protocol for a randomized controlled trial.

Delirium in the intensive care unit (ICU) affects up to 80% of critically ill, mechanically ventilated (MV) adults. Delirium is associated with substantial negative outcomes, including increased hospital complications and long-term effects on cognition and health status in ICU survivors. The purpose of this randomized controlled trial is to test the effectiveness of a Family Automated Voice Reorientation (FAVoR) intervention on delirium among critically ill MV patients. The FAVoR intervention uses scripted audio messages, which are recorded by the patient's family and played at hourly intervals during daytime hours. This ongoing orientation to the ICU environment through recorded messages in a voice familiar to the patient may enable the patient to more accurately interpret the environment and thus reduce risk of delirium. The study's primary aim is to test the effect of the FAVoR intervention on delirium in critically ill MV adults in the ICU. The secondary aims are to explore: (1) if the effect of FAVoR on delirium is mediated by sleep, (2) if selected biobehavioral factors moderate the effects of FAVoR on delirium, and (3) the effects of FAVoR on short-term and long-term outcomes, including cognition and health status. Subjects (n = 178) are randomly assigned to the intervention or control group within 48 h of initial ICU admission and intubation. The intervention group receives FAVoR over a 5-day period, while the control group receives usual care. Delirium-free days, sleep and activity, cognition, patient-reported health status and sleep quality, and data regarding iatrogenic/environmental and biobehavioral factors are collected.