The NOSTRA III trial (NO Synthase in TRAumatic Brain Injury; clinicaltrials.gov identifier NCT02794168) is a pivotal European trial assessing the efficacy and safety of ronopterin for the treatment of patients with moderate and severe TBI. Current therapeutic approaches to acute TBI are predominantly supportive measures, initiated reactively, to decrease elevated intracranial pressure with the aim of reducing mortality and morbidity. To date, no specific pharmacologic intervention has been demonstrated to improve long-term physical and cognitive recovery. The NOSTRA III trial is a placebo-controlled, randomised, double-blind, multi-centre study in five countries at 29 investigational sites in Austria, France, Germany, Spain and the UK. In total 224 eligible patients were enrolled. Ronopterin is the first drug which simultaneously targets blood vessels and tissue of the injured brain by reducing the excessive production of nitric oxide via upregulated inducible NO synthase (iNOS).

Professor Dr John Stover, Chief Medical Officer of vasopharm, explained:

“While NOSTRA III did not achieve statistical significance in the pre-specified primary endpoint of eGOS at six months after trauma, we performed a detailed hypothesis driven post-hoc analysis guided by pathophysiology combined with biochemistry and pharmacology. This analysis clearly reveals the potential of ronopterin to benefit patients when infused within the initial 12 hours after TBI. Ronopterin was associated with a higher median eGOS at 3 and 6 months vs placebo (3 months: eGOS 5 vs 4; 6 months: eGOS 6 vs 5, respectively), a larger proportion of patients with good recovery, i.e. eGOS 7 and 8 at 6 months (37% vs 23%), and a significantly higher odds ratio in patients with an increase in eGOS from 3 to 6 months (2.98; p=0.039). The Number Needed to Treat is calculated at 7 for patients with a good recovery (eGOS 7 and 8) and 4 for patients with an increase in eGOS over time. These post-hoc results of the NOSTRA III trial corroborate the positive results of the dose-finding NOSTRA II study. This efficacy, in the opinion of the Data Monitoring Committee, clearly outweighs the known adverse event profile, resulting in a positive benefit-risk assessment. We consider these results robust and clinically relevant, and vasopharm will seek scientific advice from Competent Authorities on the further regulatory pathway for ronopterin.”

Frank Tegtmeier, PhD, Chief Scientific Officer of vasopharm, commented:

“We are pleased that we have identified a clinically coherent explanation for the results of the pre-specified analysis and that we can provide a clear rationale for the beneficial use of ronopterin in patients with moderate and severe TBI. The early infusion and trajectory of improvement over time are supported by recent publications of observational studies and randomised controlled Phase III trials.”

Prof. Dr. Erich Schmutzhard, Medical University of Innsbruck, Austria and Chief Investigator for the NOSTRA III trial, said: 

“The demanding complexity of traumatic brain injury is well known, every injury is different. Experience shows us that not all patients will benefit from interventions and treatment approaches we deem helpful. In this difficult clinical context, it is remarkable that ronopterin resulted in a significantly higher number of patients with signs of improved recovery. Ronopterin is the first drug to potentially offer a new and advanced treatment option to patients with acute moderate and severe TBI. The early infusion will be easy to integrate in our daily emergency and intensive care routine.”

NOSTRA III’s primary endpoint is the extended Glasgow Outcome Scale (eGOS) at six months post trauma; the eGOS at three months after TBI is one of the secondary endpoints. The combination of these primary and secondary endpoints allows evaluation of the trajectory of neurologic recovery during the first six months after TBI, reflecting a clinically important measure and timeframe.