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Original Investigation
Caring for the Critically Ill Patient
October 2, 2019

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

Author Affiliations
  • 1Department of Critical Care Medicine, St. Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium
  • 2Berry Consultants LLC, Austin, Texas
  • 3Ferring Pharmaceuticals A/S, Copenhagen, Denmark
  • 4StraDevo A/S, Kongens Lyngby, Denmark
  • 5Medical-Surgical Intensive Care Unit, Inserm CIC1435, Dupuytren Teaching Hospital, Limoges, France
  • 6Department of Emergency Medicine, Harbor-UCLA Medical Center, Torrance, California
  • 7Los Angeles Biomedical Research Institute, Torrance, California
  • 8Department of Emergency Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
  • 9Division of Infectious Diseases, Alpert Medical School of Brown University, Providence, Rhode Island
  • 10Department of Intensive Care, Rigshospitalet, Copenhagen, Denmark
  • 11Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
  • 12Center for Heart Lung Innovation and the Division of Critical Care Medicine, St. Paul’s Hospital, University of British Columbia, Vancouver, Canada
  • 13Department of Emergency Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
  • 14Centre Hospitalier Universitaire d’Angers, Angers, France
  • 15Nordsjaellands Hospital in Hilleroed, Copenhagen, Denmark
  • 16Centre Hospitalier Régional, Hopital de La Source, Orléans, France
  • 17Fondation Hôpital Saint Joseph. Paris, France
  • 18Medical Intensive Care Unit, Nantes University Hospital, Nantes, France
  • 19Ghent University Hospital, Ghent, Belgium
  • 20CHU UCL Manur, Mont-Godinne, Yvoir, Belgium
  • 21Clinique Saint-Pierre, Ottignies, Belgium
  • 22Eastern Idaho Regional Medical Center, Idaho Falls
  • 23Centre Hospitalier Universitaire de Nîmes, Nîmes, France
  • 24Lariboisière Hospital, Paris-Diderot University, INSERM UMRS-1144, Paris, France
  • 25Centre Hospitalier Régional et Universitaire de Tours, Tours, France
  • 26Hopital Cochin, Paris, France
  • 27Centre Hospitalier Régional et Universitaire de Dijon, Dijon, France
  • 28Aalborg Universitetshospital, Aalborg, Denmark
  • 29Ziekenhuis Oost-Limburg, Genk, Belgium
  • 30Randers Regions Hospital, Randers, Denmark
  • 31Centre Hospitalier Departemental de Vendee, La Roche sur Yon, France
  • 32Bispebjerg Hospital, Copenhagen, Denmark
  • 33Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, Department of Critical Care, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 34Associate Editor, JAMA
JAMA. 2019;322(15):1476-1485. doi:10.1001/jama.2019.14607
Key Points

Question  For 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.

Abstract

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.

Trial Registration  ClinicalTrials.gov Identifier: NCT02508649

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