Title: Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock: The SEPSIS-ACT Randomized Clinical Trial
Author: Pierre-Francois Laterre, Scott M. Berry, Allan Blemings, Jan E. Carlsen, Bruno Franois, Todd Graves, Karsten Jacobsen, Roger J. Lewis, Steven M. Opal, Anders Perner, Peter Pickkers, James A. Russell, Nis A. Windelv, Donald M. Yealy, Pierre Asfar, Morten H. Bestle, Grégoire Muller, Cédric Bruel, Nolle Brulé, Johan Decruyenaere, Alain-Michel Dive, Thierry Dugernier, Kenneth Krell, Jean-Yves Lefrant, Bruno Megarbane, Emmanuelle Mercier, Jean-Paul Mira, Jean-Pierre Quenot, Bodil Steen Rasmussen, Hans-Christian Thorsen-Meyer, Margot Vander Laenen, Marianne Lauridsen Vang, Philippe Vignon, Isabelle Vinatier, Sine Wichmann, Xavier Wittebole, Anne Louise Kjlbye, Derek C. Angus
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.
Objective To 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 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.
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.