Effect of selepressin vs placebo on ventilator- and vasopressor-free days in patients with septic shock : the SEPSIS-ACT randomized clinical trial

Key Points: QuestionFor adults with septic shock treated with norepinephrine, does use of selepressin, a selective vasopressin V1a receptor agonist, compared with placebo, improve patient outcome, defined as an increase in the number of days alive and free of both ventilation and vasopressor use? Findings: In this randomized clinical trial that included 828 patients with septic shock requiring norepinephrine, treatment with selepressin compared with placebo resulted in 15.0 vs 14.4 ventilator- and vasopressor-free days within 30 days, a difference that was not statistically significant. Meaning: Treatment with selepressin was not effective in improving ventilator- and vasopressor-free days. Importance: Norepinephrine, the first-line vasopressor for septic shock, is not always effective and has important catecholaminergic adverse effects. Selepressin, a selective vasopressin V1a receptor agonist, is a noncatecholaminergic vasopressor that may mitigate sepsis-induced vasodilatation, vascular leakage, and edema, with fewer adverse effects. ObjectiveTo test whether selepressin improves outcome in septic shock. Design, Setting, and Participants: An adaptive phase 2b/3 randomized clinical trial comprising 2 parts that included adult patients (n=868) with septic shock requiring more than 5 mu g/min of norepinephrine. Part 1 used a Bayesian algorithm to adjust randomization probabilities to alternative selepressin dosing regimens and to trigger transition to part 2, which would compare the best-performing regimen with placebo. The trial was conducted between July 2015 and August 2017 in 63 hospitals in Belgium, Denmark, France, the Netherlands, and the United States, and follow-up was completed by May 2018. Interventions: Random assignment to 1 of 3 dosing regimens of selepressin (starting infusion rates of 1.7, 2.5, and 3.5 ng/kg/min; n=585) or to placebo (n=283), all administered as continuous infusions titrated according to hemodynamic parameters. Main Outcomes and Measures: Primary end point was ventilator- and vasopressor-free days within 30 days (deaths assigned zero days) of commencing study drug. Key secondary end points were 90-day mortality, kidney replacement therapy-free days, and ICU-free days. Results: Among 868 randomized patients, 828 received study drug (mean age, 66.3 years; 341 [41.2%] women) and comprised the primary analysis cohort, of whom 562 received 1 of 3 selepressin regimens, 266 received placebo, and 817 (98.7%) completed the trial. The trial was stopped for futility at the end of part 1. Median study drug duration was 37.8 hours (IQR, 17.8-72.4). There were no significant differences in the primary end point (ventilator- and vasopressor-free days: 15.0 vs 14.5 in the selepressin and placebo groups; difference, 0.6 [95% CI, -1.3 to 2.4]; P=.30) or key secondary end points (90-day mortality, 40.6% vs 39.4%; difference, 1.1% [95% CI, -6.5% to 8.8%]; P=.77; kidney replacement therapy-free days: 18.5 vs 18.2; difference, 0.3 [95% CI, -2.1 to 2.6]; P=.85; ICU-free days: 12.6 vs 12.2; difference, 0.5 [95% CI, -1.2 to 2.2]; P=.41). Adverse event rates included cardiac arrhythmias (27.9% vs 25.2% of patients), cardiac ischemia (6.6% vs 5.6%), mesenteric ischemia (3.2% vs 2.6%), and peripheral ischemia (2.3% vs 2.3%). Conclusions and Relevance: Among patients with septic shock receiving norepinephrine, administration of selepressin, compared with placebo, did not result in improvement in vasopressor- and ventilator-free days within 30 days. Further research would be needed to evaluate the potential role of selepressin for other patient-centered outcomes in septic shock. Trial Registration: ClinicalTrials.gov Identifier: NCT02508649 This phase 2b/3 randomized clinical trial compares the effects of selepressin, a selective vasopressin V1a receptor agonist and noncatecholaminergic vasopressor, vs placebo on ventilator- and vasopressor-free days within 30 days among adult patients with septic shock receiving norepinephrine