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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

Russell, James A; Vincent, Jean-Louis; Kjølbye, Anne Louise; Olsson, Håkan; Blemings, Allan; Spapen, Herbert; Carl, Peder; Laterre, Pierre-Francois and Grundemar, Lars LU (2017) In Critical care (London, England) 21.
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... (More)

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.

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keywords
Adolescent, Adult, Aged, Belgium, Child, Denmark, Double-Blind Method, Female, Humans, Hypotension/drug therapy, Male, Middle Aged, Norepinephrine/pharmacokinetics, Placebos, Receptors, Vasopressin/agonists, Shock, Septic/complications, United States, Vasoconstrictor Agents/pharmacokinetics, Vasopressins/pharmacokinetics
in
Critical care (London, England)
volume
21
publisher
BioMed Central
external identifiers
  • scopus:85027262855
ISSN
1364-8535
DOI
10.1186/s13054-017-1798-7
language
English
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no
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bf9fad1c-b848-4b7f-badc-aadd5b16e5ba
date added to LUP
2019-09-03 12:55:32
date last changed
2019-10-23 06:22:25
@article{bf9fad1c-b848-4b7f-badc-aadd5b16e5ba,
  abstract     = {<p>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.</p><p>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 &gt;60 mmHg without norepinephrine, norepinephrine dose, and proportion of patients maintaining MAP &gt;60 mmHg with or without norepinephrine over 7 days. Secondary endpoints included cumulative fluid balance, organ dysfunction, pharmacokinetics, and safety.</p><p>RESULTS: A higher proportion of the patients receiving 2.5 ng/kg/minute selepressin maintained MAP &gt;60 mmHg without norepinephrine (about 50% and 70% at 12 and 24 h, respectively) vs. 1.25 ng/kg/minute selepressin and placebo (p &lt; 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 &lt; 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 &lt; 0.001), successfully maintaining target MAP and reducing norepinephrine dose vs. placebo (first 24 h, p &lt; 0.001). Cumulative net fluid balance was lower from day 5 onward in the selepressin 2.5 ng/kg/minute group vs. placebo (p &lt; 0.05). The selepressin 2.5 ng/kg/minute group had a greater proportion of days alive and free of ventilation vs. placebo (p &lt; 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.</p><p>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.</p><p>TRIAL REGISTRATION: ClinicalTrials.gov, NCT01000649 . Registered on September 30, 2009.</p>},
  articleno    = {213},
  author       = {Russell, James A and Vincent, Jean-Louis and Kjølbye, Anne Louise and Olsson, Håkan and Blemings, Allan and Spapen, Herbert and Carl, Peder and Laterre, Pierre-Francois and Grundemar, Lars},
  issn         = {1364-8535},
  keyword      = {Adolescent,Adult,Aged,Belgium,Child,Denmark,Double-Blind Method,Female,Humans,Hypotension/drug therapy,Male,Middle Aged,Norepinephrine/pharmacokinetics,Placebos,Receptors, Vasopressin/agonists,Shock, Septic/complications,United States,Vasoconstrictor Agents/pharmacokinetics,Vasopressins/pharmacokinetics},
  language     = {eng},
  month        = {08},
  publisher    = {BioMed Central},
  series       = {Critical care (London, England)},
  title        = {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},
  url          = {http://dx.doi.org/10.1186/s13054-017-1798-7},
  volume       = {21},
  year         = {2017},
}