Oral Sabizabulin for High-Risk, Hospitalized Adults with Covid-19: Interim Analysis.

BACKGROUND: Sabizabulin is an oral, novel microtubule disruptor that has dual antiviral and anti-inflammatory activities in preclinical models. METHODS: A randomized, multicenter placebo-controlled phase 3 clinical trial was conducted with hospitalized patients with moderate to severe Covid-19 who were at high risk for acute respiratory distress syndrome (ARDS) and death. Patients were randomly assigned (2:1) to 9 mg of oral sabizabulin or placebo daily (up to 21 days). The primary end point was all-cause mortality up to day 60. Key secondary end points were days in the intensive care unit (ICU), days on mechanical ventilation, and days in the hospital. RESULTS: A total of 204 patients were randomly assigned to treatment: 134 to sabizabulin and 70 to placebo. Baseline characteristics were similar. Sabizabulin superiority was demonstrated by a planned interim analysis for the first 150 randomized patients. Sabizabulin treatment resulted in a 24.9 percentage point absolute reduction and a 55.2% relative reduction in deaths compared with placebo (odds ratio, 3.23; 95% CI confidence interval, 1.45 to 7.22; P=0.0042). The mortality rate was 20.2% (19 of 94) for sabizabulin versus 45.1% (23 of 51) for placebo. For the key secondary end points, sabizabulin treatment resulted in a 43% relative reduction in ICU days (P=0.0013), a 49% relative reduction in days on mechanical ventilation (P=0.0013), and a 26% relative reduction in days in the hospital (P=0.0277) versus placebo. Adverse and serious adverse events were lower in the sabizabulin group compared with the placebo group. CONCLUSIONS: Sabizabulin treatment resulted in a 24.9% absolute reduction in deaths compared with placebo in hospitalized patients with moderate to severe Covid-19 at high risk for ARDS and death, with a lower incidence of adverse and serious adverse events compared with placebo. (Funded by Veru, Inc.; ClinicalTrials.gov number, NCT04842747.)

Driving Pressure: Defining the Range.

BACKGROUND: Recent literature suggests that optimization of tidal driving pressure (ΔP) would be a better variable to target for lung protection at the bedside than tidal volume (VT) or plateau pressure (Pplat), the traditional indicators of ventilator-induced lung injury. However, the usual range or variability of ΔP over time for any subject category have not been defined. This study sought to document the ΔP ranges observed in current practice among mechanically ventilated subjects receiving routine care for diverse acute conditions in a community hospital environment. METHODS: This was a retrospective, observational study in a university-affiliated and house staff-aided institution with respiratory care protocols based on extant lung-protective guidelines for VT. Demographic characteristics and measured parameters related to mechanical ventilation and hemodynamics were extracted from electronic records of intubated subjects for each 8-h period of the first 24 h in the ICU. Pplat values reported by the ventilator were validated by the respiratory therapist before those data were entered into the electronic medical record. RESULTS: The mean ΔP was significantly higher at Time 1 (mean 16.1, range 7.0-31.0 cm H2O) compared to both Time 2 (mean 14.5, range 7.0-35.0 cm H2O) (P < .001) and Time 3 (mean 14.8, range 8.0-32 cm H2O) (P < .001). At all time points, the median ΔP was higher for completely passive breathing compared to triggered breathing. The widest difference between presumed entirely passive and presumed intermittently or consistently triggered breaths occurred at Time 1 (mean ΔP = 17.2 vs 14.9 cm H2O, respectively) (P = .01). CONCLUSIONS: Suggested safety thresholds for ΔP are often violated by a strategy that focuses on only VT and Pplat. Our data suggest that ΔP is lower for passive versus triggered breathing cycles. Vigilance is especially important in the initial stages of mechanical ventilator support, and attention should be paid to triggering efforts when interpreting and comparing machine-determined numerical values for ΔP.