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

Background: Vasopressin 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.

Methods: This 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.

Results: A 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.

Conclusions: In 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 registration: ClinicalTrials.gov, NCT01000649 . Registered on September 30, 2009.

Keywords: Fluid balance; Mechanical ventilation; Norepinephrine; Selepressin; Septic shock; V1A agonist.

Conflict of interest statement

Ethics approval and consent to participate

The study protocol and informed consent documents were approved by the independent ethics committees or research ethics boards of all participating institutions, and written informed consent was obtained from all patients, their next of kin, or another surrogate decision maker, as appropriate prior to enrollment. The study was also approved by the competent regulatory authorities of each country participating in the trial.

Consent for publication

Informed written consent was received for publication of the manuscript and figures.

Competing interests

JAR reports patents owned by the University of British Columbia (UBC) that are related to PCSK9 inhibitor(s) and sepsis and related to the use of vasopressin in septic shock. JAR is an inventor on these patents. JAR is a founder, director, and shareholder in Cyon Therapeutics Inc. (developing a sepsis therapy). JAR has share options in Leading BioSciences Inc. JAR is a shareholder in Molecular You Corp. JAR reports receiving consulting fees from Cubist Pharmaceuticals (now owned by Merck; formerly was Trius Pharmaceuticals; developing antibiotics), Leading BioSciences Inc. (developing a sepsis therapeutic), Ferring Pharmaceuticals (manufacturer of vasopressin and developing selepressin), Grifols (seller of albumin), La Jolla Pharmaceutical Co. (developing angiotensin II; JAR chairs the data safety and monitoring board of a trial of angiotensin II), CytoVale Inc. (developing a sepsis diagnostic), and Asahi Kasei Pharma America (AKPA; developing recombinant thrombomodulin). JAR reports having received an investigator-initiated grant from Grifols that is provided to and administered by UBC. HO, ALK, LG, and AB are employees of Ferring Pharmaceuticals A/S. JLV is editor-in-chief of Critical Care. JLV, HS, PC, and PFL declare that they have no competing interests.

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Figures

Fig. 1

Consolidated Standards of Reporting Trials (CONSORT) diagram of patient flow through the study

Fig. 2

Proportion of patients maintaining a mean arterial pressure >60 mmHg without any open-label norepinephrine support at the indicated time points. The difference between 2.5 ng/kg/minute and placebo was statistically significant (p 

Fig. 3

Mean cumulative amount (a) and infusion rate (b) of open-label norepinephrine over time in septic shock patients. Selepressin and placebo were infused at a constant rate as indicated, whereas norepinephrine was weaned as fast as possible while still keeping the target treatment mean arterial pressure ≥65 mmHg. Numbers at the bottom of the figure indicate number of patients at each time point. Bars indicate SD. Pl Placebo, 1.25 1.25 ng/kg/minute, 2.5 2.5 ng/kg/minute

Fig. 4

Mean cumulative net fluid balance over 7 days from start of selepressin/placebo treatment. Selepressin and placebo were infused at a constant rate as indicated. Numbers at the bottom of the figure indicate number of patients at each time point. Bars indicate SD. Pl Placebo, 1.25 1.25 ng/kg/minute, 2.5 2.5 ng/kg/minute