Selepressin, a novel selective vasopressin V1A agonist, is an effective substitute for norepinephrine in a phase IIa randomized, placebo-controlled trial in septic shock patients

Abstract

BackgroundVasopressin is widely used for vasopressor support in septic shock patients, but experimental evidence suggests that selective V1A agonists are superior. The initial pharmacodynamic effects, pharmacokinetics, and safety of selepressin, a novel V1A-selective vasopressin analogue, was examined in a phase IIa trial in septic shock patients.MethodsThis was a randomized, double-blind, placebo-controlled multicenter trial in 53 patients in early septic shock (aged ≥18 years, fluid resuscitation, requiring vasopressor support) who received selepressin 1.25 ng/kg/minute (n = 10), 2.5 ng/kg/minute (n = 19), 3.75 ng/kg/minute (n = 2), or placebo (n = 21) until shock resolution or a maximum of 7 days. If mean arterial pressure (MAP) ≥65 mmHg was not maintained, open-label norepinephrine was added. Co-primary endpoints were maintenance of MAP >60 mmHg without norepinephrine, norepinephrine dose, and proportion of patients maintaining MAP >60 mmHg with or without norepinephrine over 7 days. Secondary endpoints included cumulative fluid balance, organ dysfunction, pharmacokinetics, and safety.ResultsA higher proportion of the patients receiving 2.5 ng/kg/minute selepressin maintained MAP >60 mmHg without norepinephrine (about 50% and 70% at 12 and 24 h, respectively) vs. 1.25 ng/kg/minute selepressin and placebo (p < 0.01). The 7-day cumulative doses of norepinephrine were 761, 659, and 249 μg/kg (placebo 1.25 ng/kg/minute and 2.5 ng/kg/minute, respectively; 2.5 ng/kg/minute vs. placebo; p < 0.01). Norepinephrine infusion was weaned more rapidly in selepressin 2.5 ng/kg/minute vs. placebo (0.04 vs. 0.18 μg/kg/minute at 24 h, p < 0.001), successfully maintaining target MAP and reducing norepinephrine dose vs. placebo (first 24 h, p < 0.001). Cumulative net fluid balance was lower from day 5 onward in the selepressin 2.5 ng/kg/minute group vs. placebo (p < 0.05). The selepressin 2.5 ng/kg/minute group had a greater proportion of days alive and free of ventilation vs. placebo (p < 0.02). Selepressin (2.5 ng/kg/minute) was well tolerated, with a similar frequency of treatment-emergent adverse events for selepressin 2.5 ng/kg/minute and placebo. Two patients were infused at 3.75 ng/kg/minute, one of whom had the study drug infusion discontinued for possible safety reasons, with subsequent discontinuation of this dose group.ConclusionsIn septic shock patients, selepressin 2.5 ng/kg/minute was able to rapidly replace norepinephrine while maintaining adequate MAP, and it may improve fluid balance and shorten the time of mechanical ventilation.Trial registrationClinicalTrials.gov, NCT01000649. Registered on September 30, 2009.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-017-1798-7) contains supplementary material, which is available to authorized users.

Shock – Classification and Pathophysiological Principles of Therapeutics

“…It has been shown that selepressin at an infusion rate of 2.5 ng/kg/minute rapidly replaced norepinephrine while maintaining target MAP and may have improved fluid balance and shortened the time of mechanical ventilation. Further studies of selepressin’s mechanism of action and additional larger randomized controlled trials to investigate its efficacy are needed and ongoing to assess its ability to improve the treatment outcome of patients in septic shock [ 76 ].…”

Tight junction structure, function, and assessment in the critically ill: a systematic review

“…Many anti-cytokine therapies, such as antibodies that target vascular endothelial growth factor or neutralize lipopolysaccharide signaling, have not shown clinical benefit, likely due to complex, time-dependent, and overlapping pathways. Recent trials involving agents that may tighten vascular barriers, such as those that modulate vasopressin [ 67 , 68 ] and adrenomedullin pathways [ 69 , 70 ], are more promising. It is possible that these therapies may counter-act the systemic signaling that leads to TJ disruption in endothelium and epithelium, although additional translational research is required.…”

Review article: Sepsis in the emergency department – Part 3: Treatment

“…55 A small phase IIb human study has been recently completed, finding selepressin a safe and effective noradrenaline-sparing agent, with potential additional benefits. 56 Finally, angiotensin II also reduced noradrenaline requirements for septic shock patients in the recent ATHOS-3 RCT. 57 As with selepressin, further studies are required to demonstrate mortality and organ function benefits.…”

“…Selepressin activates V1a receptors even more selectively, with potential to reduce important V2‐mediated effects such as fluid accumulation and vascular leakage . A small phase IIb human study has been recently completed, finding selepressin a safe and effective noradrenaline‐sparing agent, with potential additional benefits . Finally, angiotensin II also reduced noradrenaline requirements for septic shock patients in the recent ATHOS‐3 RCT .…”