Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock: The SEPSIS-ACT Randomized Clinical Trial

Key PointsQuestionFor 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? FindingsIn 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. MeaningTreatment with selepressin was not effective in improving ventilator- and vasopressor-free days. ImportanceNorepinephrine, 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 ParticipantsAn 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. InterventionsRandom 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 MeasuresPrimary 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. ResultsAmong 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 RelevanceAmong 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 RegistrationClinicalTrials.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.