NOSTRA III registration TRIAL
The NOSTRA (NOSynthase Inhibition in TRAumatic brain injury) III trial entitled “Efficacy of VAS203 in patients with moderate and severe traumatic brain injury (NOSTRA Phase III trial)” (NCT02794168) examined the efficacy and safety of VAS203 in patients with an acute moderate and severe traumatic brain injury (TBI).
The placebo-controlled, randomised, double-blind, multi-centre NOSTRA III trial was conducted in 38 centers in 5 European countries (Austria, France, Germany, Spain, United Kingdom) and completed as planned. The first patient was enrolled on 24 August 2016 and the study was completed on 17 June 2020.
In total 223 patients comprise the Full Analysis Set with 112 patients randomized to the VAS203 treatment arm and 111 patients in the Placebo treatment arm. As in the NOSTRA II trial, VAS203 was added to the Standard of Care.
During the entire course of the study, an independent Drug Monitoring Committee (DMC) unanimously recommended to continue the study according to the original study protocol.
The DMC concluded that at no time any safety concerns were identified.
Primary endpoint- prespecified analysis
The prespecified analysis revealed an equipoise in the primary endpoint (extended Glasgow Outcome Score) at 6 months in both treatment arms. Based on the stratification by age, eGOS was significantly higher in the patients 18-39 years of age compared to 40-60 years with a median difference of 2 eGOS levels (p<0.001), indicating a difference in recovery in favour of patients aged < 40 years of age.
Post hoc analysis of NOSTRA III trial
The post hoc analysis revealed clinically meaningful and statistically significant differences between placebo and verum group in favour of a beneficial action of the drug. This data is currently the basis for a new patent application and will be disclosed after its submission. Consequently, whilst the company is eager and willing to discuss this data with interested parties, the data can only be disclosed under NDA.
NOSTRA II Proof-of-Concept trial
NOSTRA II was an exploratory placebo-controlled, randomised, multi-centre study comparing VAS203 to placebo, in addition to standard of care. The trial was conducted in six centres in Austria, France, Spain, Switzerland. and the UK. VAS203 treated patients had a significantly better clinical outcome than patients given placebo, as assessed by the therapy intensity level (at day 6 after TBI) and the extended Glasgow Outcome Score (at months 6 and 12 after TBI). These trial results strongly indicate a neuroprotective role of VAS203 in patients with moderate and severe TBI.
NOSTRA II also assessed cerebral pharmacokinetics (PK) and pharmacodynamic markers (PD) by analysing cerebral microdialysate samples. VAS203 and its metabolites were detected in these samples, reflecting a dose dependent increase and persistence of the metabolites up to 3 days after stopping the continuous infusion of VAS203. PD data in cerebral microdialysate samples reflect pharmacologic inhibition of iNOS. As a consequence of the iNOS inhibition, cerebral microdialysate glutamate levels were significantly reduced.
Tegtmeier F, Schinzel R, Beer R, Bulters D, LeFrant JY, Sahuquillo J, Unterberg A, Andrews P, Belli A, Ibanez J, Lagares A, Mokry M, Willschke H, Flüh C, Schmutzhard E; NOSTRA Investigators. Efficacy of Ronopterin (VAS203) in Patients with Moderate and Severe Traumatic Brain Injury (NOSTRA phase III trial): study protocol of a confirmatory, placebo-controlled, randomised, double blind, multi-centre study. Trials. 2020 Jan 14;21(1):80. doi: 10.1186/s13063-019-3965-4.
Ott C, Bosch A, Winzer N, Friedrich S, Schinzel R, Tegtmeier F, Schmieder RE. Effects of the nitric oxide synthase inhibitor ronopterin (VAS203) on renal function in healthy volunteers. Br J Clin Pharmacol. 2019 Jan 21. doi:10.1111/bcp.13870.
Schinzel R. and Tegtmeier F; Chapter 8 - Nitric Oxide Synthase Inhibitors in Traumatic Brain Injury, In New Therapeutics for Traumatic Brain Injury, edited by Kim A. Heidenreich,, Academic Press, San Diego, 2017, Pages 133-144, ISBN 9780128026861,
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Stover JF, Belli A, Boret H, Bulters D, Sahuquillo J, Schmutzhard E, Zavala E, Ungerstedt U, Schinzel R, Tegtmeier F; 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). J Neurotrauma. 2014 Oct 1;31(19):1599-606. doi: 10.1089/neu.2014.3344.
Terpolilli NA, Zweckberger K, Trabold R, Schilling L, Schinzel R, Tegtmeier F, Plesnila N. The novel nitric oxide synthase inhibitor 4-amino-tetrahydro-L-biopterine prevents brain edema formation and intracranial hypertension following traumatic brain injury in mice. J Neurotrauma. 2009 Nov;26(11):1963-75. doi: 10.1089/neu.2008-0853.