Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock

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 PARTICIPANTSAn 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 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. 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,). 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;

Vasopressin and its analogues in shock states: a review

“…Recently, the SEPSISACT study [50] compared with a randomized placebo-controlled trial the addition of selepressin to norepinephrine. This study was divided in two parts: the first was aimed at assessing the best-performing regimen of selepressin (between three dosing regimens of selepressin), and, in the second part, the authors compared this selepressin regimen to placebo.…”

Non-catecholamine vasopressors in the treatment of adult patients with septic shock—evidence from meta-analysis and trial sequential analysis of randomized clinical trials

“…Up to April 30, 2020, we initially retrieved 807 records and 23 trials reporting on 4380 septic shock patients were eligible for final analysis (21 full-text articles and 2 abstracts). These papers were from Austria [ 30 ] ( n = 1), France [ 24 ] ( n = 1), Iran [ 22 ] ( n = 1), Czech Republic [ 16 ] ( n = 1), England [ 18 ] ( n = 1), Colombia [ 21 ] ( n = 1), Brazil [ 13 , 31 ] ( n = 2), India [ 15 , 32 ] ( n = 2), Italy [ 25 , 26 ] ( n = 2), the USA [ 23 , 33 ] ( n = 2), China [ 14 , 19 , 27 , 28 ] ( n = 4), and multi-country [ 4 , 11 , 17 , 20 , 34 ] ( n = 5). All these trials from ICUs were published from 2003 to 2019, and the mean age was from 47.53 to 72.83 years.…”

“…Nevertheless, achieving the target MAP may generally require high doses of NE, increasing the risk of myocardial, mesenteric, and digital ischemia as well as arrhythmias and mortality, etc. [ 4 , 5 ]. Regrettably, around 7% critically ill patients tend to be unresponsive to the increasing dose of NE (refractory shock) in spite of an early recognition, diagnosis, and treatment, with over 50% short-term mortality [ 6 ].…”

Contemporary strategies to improve clinical trial design for critical care research: insights from the First Critical Care Clinical Trialists Workshop

“…Many of these adaptive methodologies are applicable to clinical trials in critical care. Recent examples of adaptive design features in critical care include the RACE trial [37], an adaptive, dose-finding, phase 2 clinical trial of levocarnitine for septic shock, the SEPSIS-ACT trial of selepressin for septic shock [38], and the phase 3 PROSpect trial (NCT03896763). The PROSpect trial plans to randomize pediatric patients with ARDS to supine or prone positioning and low tidal volume or high-frequency ventilation, with adjustments in the enrollment ratios occurring every 100 patients.…”