Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock: The SEPSIS-ACT Randomized Clinical Trial
Open accessAbstract
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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There are data from RCTs on short versus long courses in specific conditions such as pneumonia, urinary tract infections, bacteremia, and intraabdominal infections.
“There are data from RCTs in specific conditions such as pneumonia (286-289), urinary tract infections (290), bacteremia (291, 292), and intraabdominal infections (293).”
From Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. (2021) · cites this paper as [289]
The Trial Design and Oversight section describes a randomized comparison of selepressin and placebo for septic shock, not short versus long treatment courses. The End Points section and infection-site table do not report antibiotic-duration trials for pneumonia, urinary tract infections, bacteremia, or intra-abdominal infections. Searches for short versus long courses and antibiotic-treatment duration found no passage addressing the claim; page numbers were unavailable in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredA phase IIb/III selepressin trial was stopped for futility after 828 patients with no significant differences in key endpoints including ventilator- and vasopressor-free days, 90-day mortality, RRT-free days, and ICU-free days.
“The study was stopped for futility after enrolment of 828 patients, with no significant differences between any of the key endpoints [ventilator- and vasopressor-free days, 15.0 (selepressin) versus 14.5 (placebo), p = 0.30; 90-day all-cause mortality, 40.6% vs 39.4%, p = 0.77; 30-day RRT-free days, 18.5 vs 18.2, p = 0.85; 30-day ICU-free days, 12.6 vs 12.2, p = 0.41]; adverse event rates were als”
From Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (2021) · cites this paper as [364]
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- Authors
- Laterre, P.-F., Berry, S. M., Blemings, A., Carlsen, J. E., François, B., Graves, T., Jacobsen, K., Lewis, R. J., Opal, S. M., Perner, A., Pickkers, P., Russell, J. A., Windeløv, N. A., Yealy, D. M., Asfar, P., Bestle, M. H., Muller, G., Bruel, C., Brulé, N., Decruyenaere, J., Dive, A.-M., Dugernier, T., Krell, K., Lefrant, J.-Y., Megarbane, B., Mercier, E., Mira, J.-P., Quenot, J.-P., Rasmussen, B. S., Thorsen-Meyer, H.-C., Vander Laenen, M., Vang, M. L., Vignon, P., Vinatier, I., Wichmann, S., Wittebole, X., Kjølbye, A. L., Angus, D. C., & for the SEPSIS-ACT Investigators
- Affiliations
- Department of Critical Care Medicine, St. Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium
- Berry Consultants, LLC (United States) (US)
- Ferring Pharmaceuticals (Denmark) (DK)
- StraDevo A/S, Kongens Lyngby, Denmark
- Inserm (FR)
- University of California, Los Angeles (US)
- Brown University (US)
- Rigshospitalet (DK)
- Radboud University Medical Center (NL)
- University of British Columbia (CA)
- University of Pittsburgh (US)
- Centre Hospitalier Universitaire d'Angers (FR)
- Nordsjællands Hospital (DK)
- Centre Hospitalier Régional, Hopital de La Source, Orléans, France
- Fondation Hôpital Saint-Joseph (FR)
- Medical Intensive Care Unit, Nantes University Hospital, Nantes, France
- Ghent University Hospital (BE)
- CHU UCL Manur, Mont-Godinne, Yvoir, Belgium
- Clinique Saint Pierre (BE)
- Eastern Idaho Regional Medical Center, Idaho Falls
- Centre Hospitalier Universitaire de Nîmes (FR)
- Lariboisière Hospital, Paris-Diderot University, INSERM UMRS-1144, Paris, France
- Centre Hospitalier Universitaire de Tours (FR)
- Hôpital Cochin (FR)
- CHU Dijon Bourgogne (FR)
- Aalborg University Hospital (DK)
- Department of Intensive Care, Rigshospitalet, Copenhagen, Denmark
- Ziekenhuis Oost-Limburg, Genk, Belgium
- Regional Hospital Randers (DK)
- Centre Hospitalier Départemental Vendée (FR)
- Bispebjerg Hospital (DK)
- UCLouvain (BE)
- Corresponding author
- Angus, Derek C.
- ORCID
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2019-10-15
- Volume
- 322
- Issue
- 15
- Pages
- 1476
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC6802260
- OpenAlex
- W2978101814
- Cited by
- 147
- References
- 25
- Citations by year
- 2026: 18 · 2025: 15 · 2024: 17 · 2023: 24 · 2022: 19 · 2021: 26 · 2020: 25 · 2019: 3
- FWCI
- 13.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- HAL (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- DIAL (Catholic University of Leuven) (submittedVersion, other-oa)
- VBN Forskningsportal (Aalborg Universitet) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Health Sciences › Medicine › Surgery › Hemodynamic Monitoring and Therapy
- Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
- Keywords
- septic shock, norepinephrine, vasopressor-free days, ventilator-free days, sepsis mortality, renal replacement therapy, ICU-free days, Bayesian adaptive randomization, futility stopping, dosing regimen, sepsis
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