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

Abstract

Importance\nNorepinephrine, 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.\n\n\nObjective\nTo test whether selepressin improves outcome in septic shock.\n\n\nDesign, Setting, and Participants\nAn adaptive phase 2b/3 randomized clinical trial comprising 2 parts that included adult patients (n\u2009=\u2009868) with septic shock requiring more than 5 μg/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.\n\n\nInterventions\nRandom assignment to 1 of 3 dosing regimens of selepressin (starting infusion rates of 1.7, 2.5, and 3.5 ng/kg/min; n\u2009=\u2009585) or to placebo (n\u2009=\u2009283), all administered as continuous infusions titrated according to hemodynamic parameters.\n\n\nMain Outcomes and Measures\nPrimary 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.\n\n\nResults\nAmong 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\u2009=\u2009.30) or key secondary end points (90-day mortality, 40.6% vs 39.4%; difference, 1.1% [95% CI, -6.5% to 8.8%]; P\u2009=\u2009.77; kidney replacement therapy-free days: 18.5 vs 18.2; difference, 0.3 [95% CI, -2.1 to 2.6]; P\u2009=\u2009.85; ICU-free days: 12.6 vs 12.2; difference, 0.5 [95% CI, -1.2 to 2.2]; P\u2009=\u2009.41). 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%).\n\n\nConclusions and Relevance\nAmong 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.\n\n\nTrial Registration\nClinicalTrials.gov Identifier: NCT02508649.