Nitric oxide synthase inhibition with the antipterin VAS203 improves outcome in moderate and severe traumatic brain injury: a placebo-controlled randomized Phase IIa trial (NOSTRA)

Research output: Contribution to journalArticle

Standard

Nitric oxide synthase inhibition with the antipterin VAS203 improves outcome in moderate and severe traumatic brain injury : a placebo-controlled randomized Phase IIa trial (NOSTRA). / Stover, John F; Belli, Antonio; Boret, Henry; Bulters, Diederik; Sahuquillo, Juan; Schmutzhard, Erich; Zavala, Elisabeth; Ungerstedt, Urban; Schinzel, Reinhard; Tegtmeier, Frank; NOSTRA Investigators.

In: Journal of Neurotrauma, Vol. 31, No. 19, 01.10.2014, p. 1599-606.

Research output: Contribution to journalArticle

Harvard

Stover, JF, Belli, A, Boret, H, Bulters, D, Sahuquillo, J, Schmutzhard, E, Zavala, E, Ungerstedt, U, Schinzel, R, Tegtmeier, F & NOSTRA Investigators 2014, 'Nitric oxide synthase inhibition with the antipterin VAS203 improves outcome in moderate and severe traumatic brain injury: a placebo-controlled randomized Phase IIa trial (NOSTRA)', Journal of Neurotrauma, vol. 31, no. 19, pp. 1599-606. https://doi.org/10.1089/neu.2014.3344

APA

Stover, J. F., Belli, A., Boret, H., Bulters, D., Sahuquillo, J., Schmutzhard, E., Zavala, E., Ungerstedt, U., Schinzel, R., Tegtmeier, F., & NOSTRA Investigators (2014). Nitric oxide synthase inhibition with the antipterin VAS203 improves outcome in moderate and severe traumatic brain injury: a placebo-controlled randomized Phase IIa trial (NOSTRA). Journal of Neurotrauma, 31(19), 1599-606. https://doi.org/10.1089/neu.2014.3344

Vancouver

Author

Stover, John F ; Belli, Antonio ; Boret, Henry ; Bulters, Diederik ; Sahuquillo, Juan ; Schmutzhard, Erich ; Zavala, Elisabeth ; Ungerstedt, Urban ; Schinzel, Reinhard ; Tegtmeier, Frank ; NOSTRA Investigators. / Nitric oxide synthase inhibition with the antipterin VAS203 improves outcome in moderate and severe traumatic brain injury : a placebo-controlled randomized Phase IIa trial (NOSTRA). In: Journal of Neurotrauma. 2014 ; Vol. 31, No. 19. pp. 1599-606.

Bibtex

@article{696cc5e91e2548b39d0d15cb4532ee94,
title = "Nitric oxide synthase inhibition with the antipterin VAS203 improves outcome in moderate and severe traumatic brain injury: a placebo-controlled randomized Phase IIa trial (NOSTRA)",
abstract = "Traumatic brain injury (TBI) is an important cause of death and disability. Safety and pharmacodynamics of 4-amino-tetrahydrobiopterin (VAS203), a nitric oxide (NO)-synthase inhibitor, were assessed in TBI in an exploratory Phase IIa study (NOSynthase Inhibition in TRAumatic brain injury=NOSTRA). The study included 32 patients with TBI in six European centers. In a first open Cohort, eight patients received three 12-h intravenous infusions of VAS203 followed by a 12-h infusion-free interval over 3 days (total dose 15 mg/kg). Patients in Cohorts 2 and 3 (24) were randomized 2:1 to receive either VAS203 or placebo as an infusion for 48 or 72 h, respectively (total dose 20 and 30 mg/kg). Effects of VAS203 on intracranial pressure (ICP), cerebral perfusion pressure (CPP), brain metabolism using microdialysis, and the therapy intensity level (TIL) were end points. In addition, exploratory analysis of the extended Glasgow Outcome Score (eGOS) after 6 months was performed. Metabolites of VAS203 were detected in cerebral microdialysates. No significant differences between treatment and placebo groups were observed for ICP, CPP, and brain metabolism. TIL on day 6 was significantly decreased (p<0.04) in the VAS203 treated patients. The eGOS after 6 months was significantly higher in treated patients compared with placebo (p<0.01). VAS203 was not associated with hepatic, hematologic, or cardiac toxic effects. At the highest dose administered, four of eight patients receiving VAS203 showed transitory acute kidney injury (stage 2-3). In conclusion, the significant improvement in clinical outcome indicates VAS203-mediated neuroprotection after TBI. At the highest dose, VAS203 is associated with a risk of acute kidney injury.",
keywords = "Adult, Aged, Biopterin, Brain Injuries, Enzyme Inhibitors, Female, Glasgow Outcome Scale, Humans, Intracranial Pressure, Male, Microdialysis, Middle Aged, Neuroprotective Agents, Nitric Oxide Synthase, Young Adult",
author = "Stover, {John F} and Antonio Belli and Henry Boret and Diederik Bulters and Juan Sahuquillo and Erich Schmutzhard and Elisabeth Zavala and Urban Ungerstedt and Reinhard Schinzel and Frank Tegtmeier and {NOSTRA Investigators}",
year = "2014",
month = oct
day = "1",
doi = "10.1089/neu.2014.3344",
language = "English",
volume = "31",
pages = "1599--606",
journal = "Journal of Neurotrauma",
issn = "0897-7151",
publisher = "Mary Ann Liebert",
number = "19",

}

RIS

TY - JOUR

T1 - Nitric oxide synthase inhibition with the antipterin VAS203 improves outcome in moderate and severe traumatic brain injury

T2 - a placebo-controlled randomized Phase IIa trial (NOSTRA)

AU - Stover, John F

AU - Belli, Antonio

AU - Boret, Henry

AU - Bulters, Diederik

AU - Sahuquillo, Juan

AU - Schmutzhard, Erich

AU - Zavala, Elisabeth

AU - Ungerstedt, Urban

AU - Schinzel, Reinhard

AU - Tegtmeier, Frank

AU - NOSTRA Investigators

PY - 2014/10/1

Y1 - 2014/10/1

N2 - Traumatic brain injury (TBI) is an important cause of death and disability. Safety and pharmacodynamics of 4-amino-tetrahydrobiopterin (VAS203), a nitric oxide (NO)-synthase inhibitor, were assessed in TBI in an exploratory Phase IIa study (NOSynthase Inhibition in TRAumatic brain injury=NOSTRA). The study included 32 patients with TBI in six European centers. In a first open Cohort, eight patients received three 12-h intravenous infusions of VAS203 followed by a 12-h infusion-free interval over 3 days (total dose 15 mg/kg). Patients in Cohorts 2 and 3 (24) were randomized 2:1 to receive either VAS203 or placebo as an infusion for 48 or 72 h, respectively (total dose 20 and 30 mg/kg). Effects of VAS203 on intracranial pressure (ICP), cerebral perfusion pressure (CPP), brain metabolism using microdialysis, and the therapy intensity level (TIL) were end points. In addition, exploratory analysis of the extended Glasgow Outcome Score (eGOS) after 6 months was performed. Metabolites of VAS203 were detected in cerebral microdialysates. No significant differences between treatment and placebo groups were observed for ICP, CPP, and brain metabolism. TIL on day 6 was significantly decreased (p<0.04) in the VAS203 treated patients. The eGOS after 6 months was significantly higher in treated patients compared with placebo (p<0.01). VAS203 was not associated with hepatic, hematologic, or cardiac toxic effects. At the highest dose administered, four of eight patients receiving VAS203 showed transitory acute kidney injury (stage 2-3). In conclusion, the significant improvement in clinical outcome indicates VAS203-mediated neuroprotection after TBI. At the highest dose, VAS203 is associated with a risk of acute kidney injury.

AB - Traumatic brain injury (TBI) is an important cause of death and disability. Safety and pharmacodynamics of 4-amino-tetrahydrobiopterin (VAS203), a nitric oxide (NO)-synthase inhibitor, were assessed in TBI in an exploratory Phase IIa study (NOSynthase Inhibition in TRAumatic brain injury=NOSTRA). The study included 32 patients with TBI in six European centers. In a first open Cohort, eight patients received three 12-h intravenous infusions of VAS203 followed by a 12-h infusion-free interval over 3 days (total dose 15 mg/kg). Patients in Cohorts 2 and 3 (24) were randomized 2:1 to receive either VAS203 or placebo as an infusion for 48 or 72 h, respectively (total dose 20 and 30 mg/kg). Effects of VAS203 on intracranial pressure (ICP), cerebral perfusion pressure (CPP), brain metabolism using microdialysis, and the therapy intensity level (TIL) were end points. In addition, exploratory analysis of the extended Glasgow Outcome Score (eGOS) after 6 months was performed. Metabolites of VAS203 were detected in cerebral microdialysates. No significant differences between treatment and placebo groups were observed for ICP, CPP, and brain metabolism. TIL on day 6 was significantly decreased (p<0.04) in the VAS203 treated patients. The eGOS after 6 months was significantly higher in treated patients compared with placebo (p<0.01). VAS203 was not associated with hepatic, hematologic, or cardiac toxic effects. At the highest dose administered, four of eight patients receiving VAS203 showed transitory acute kidney injury (stage 2-3). In conclusion, the significant improvement in clinical outcome indicates VAS203-mediated neuroprotection after TBI. At the highest dose, VAS203 is associated with a risk of acute kidney injury.

KW - Adult

KW - Aged

KW - Biopterin

KW - Brain Injuries

KW - Enzyme Inhibitors

KW - Female

KW - Glasgow Outcome Scale

KW - Humans

KW - Intracranial Pressure

KW - Male

KW - Microdialysis

KW - Middle Aged

KW - Neuroprotective Agents

KW - Nitric Oxide Synthase

KW - Young Adult

U2 - 10.1089/neu.2014.3344

DO - 10.1089/neu.2014.3344

M3 - Article

C2 - 24831445

VL - 31

SP - 1599

EP - 1606

JO - Journal of Neurotrauma

JF - Journal of Neurotrauma

SN - 0897-7151

IS - 19

ER -