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Based on these results the NOSTRA Phase III trial (EudraCT no. 2013-003368-29; ClinicalTrials.gov identifier NCT02794168) is underway to test VAS203 as an acute treatment for moderate and severe TBI administered in addition to standard of care. The trial is planned to recruit 232 patients (study is expected to be completed with 220 evaluable patients in full analysis set) who meet the following key criteria: • Non-penetrating head trauma within the last 18 hours (infusion must not start earlier than six hours after the injury); • Glasgow Coma Score > 3 requiring intracranial pressure monitoring (intraventricular or intraparenchymal) according to the assessment of the treating physician; • At least one reactive pupil; • Systolic blood pressure > 100 mmHg; • 18 to 60 years of age; • More than 24 hours expected survival. With at least 30 sites in Europe (Austria, France, Germany, Spain and United Kingdom), study participants will be randomized in a one-to-one allocation to receive VAS203 or placebo, respectively. The treatment is administered as a continuous intravenous constant-rate infusion over 48 hours in addition to standard of care. The acute clinical period for each patient will be 14 days followed by a six months observation (post-clinical follow-up) period. The entire trial is planned to last 30 months including the post clinical follow-up period for the evaluation of the extended Glasgow Outcome Scale Interview (eGOS-I) as primary efficacy objective at six months after TBI. While eGOS accurately captures global outcome, it may fail to assess subtle differences in disabilities as well as recovery over a broad range of functioning. Therefore, a set of secondary objectives will evaluate the efficacy of VAS203 on the daily calculated therapy intensity level over 14 days after the trauma and on the quality of life (QoL) at three and six month after TBI applying instruments specifically developed to assess health-related QoL of TBI patients (i.e., QOLIBRI and QOLIBRI-OS). NOSTRA Phase III clinical trial started patient enrollment in August 2016. After 110 full analysis set-evaluable patients will have received their final assessment of clinical outcome, an unblinded interim analysis will be conducted by the data monitoring committee. Professor Erich Schmutzhard, head of the Neurocritical Care Unit, Medical University of Innsbruck, Austria, and coordinating investigator of the NOSTRA Phase III trial, is very excited about the launch of this clinical study: “The lack of specific treatment for TBI in spite of decades of intense research has been disappointing; however, I am optimistic that with the novel intravenous NO synthase inhibitor VAS203, a potential intervention with significant promise for severely head injured patients could be relatively close.” REFERENCES: For additional reading on the exploratory clinical phase II trial, please see: 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. CT of the head shows illustration of VAS203 in injured brain 11


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