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

Authors

  • John F Stover
  • Tony Belli
  • Henry Boret
  • Diederik Bulters
  • Juan Sahuquillo
  • Erich Schmutzhard
  • Elisabeth Zavala
  • Urban Ungerstedt
  • Reinhard Schinzel
  • Frank Tegtmeier
  • NOSTRA Investigators

Colleges, School and Institutes

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.

Details

Original languageEnglish
Pages (from-to)1599-606
Number of pages8
JournalJournal of Neurotrauma
Volume31
Issue number19
Publication statusPublished - 1 Oct 2014

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