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
(2017) In Critical Care 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.
(Less)
- author
- Russell, James A ; Vincent, Jean-Louis ; Kjølbye, Anne Louise ; Olsson, Håkan ; Blemings, Allan ; Spapen, Herbert ; Carl, Peder ; Laterre, Pierre-Francois and Grundemar, Lars LU
- publishing date
- 2017-08-15
- type
- Contribution to journal
- publication status
- published
- subject
- 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
- volume
- 21
- article number
- 213
- publisher
- BioMed Central (BMC)
- external identifiers
-
- pmid:28807037
- scopus:85027262855
- ISSN
- 1364-8535
- DOI
- 10.1186/s13054-017-1798-7
- language
- English
- LU publication?
- no
- id
- bf9fad1c-b848-4b7f-badc-aadd5b16e5ba
- date added to LUP
- 2019-09-03 12:55:32
- date last changed
- 2024-05-28 22:54:54
@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 >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.</p><p>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.</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>}},
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}},
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}},
language = {{eng}},
month = {{08}},
publisher = {{BioMed Central (BMC)}},
series = {{Critical Care}},
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}},
doi = {{10.1186/s13054-017-1798-7}},
volume = {{21}},
year = {{2017}},
}