Clinical trial NCT02794168: Efficacy of VAS203 (Ronopterin) in Patients With Moderate and Severe Traumatic Brain Injury
Official title: Efficacy of VAS203 (Ronopterin) in Patients With Moderate and Severe Traumatic Brain Injury - (NOSTRA Phase III Trial): A Confirmatory, Placebo-controlled, Randomised, Double Blind, Multi-centre Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Traumatic Brain Injury
Lead sponsor: veriNOS operations GmbH
Sponsor class: INDUSTRY
Collaborators: name: ICON plc
First posted: 2016-06-08
Enrollment: 224
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study evaluates the efficacy of an infusion of Ronopterin (VAS203) on clinical outcome in patients with moderate and severe traumatic brain injury. Half of the participants will receive Ronopterin (VAS203), while the other half will receive placebo.

Detailed description: Severe and moderate traumatic brain injury (TBI) constitutes a major health problem. TBI is the leading cause of death and disability among young adults in developed countries, and the incidence in the elderly population is increasing.

Neurological damage after TBI is caused not only by the accident itself, but evolves afterwards. The posttraumatic secondary injury includes - among others - inflammation and oedema formation with subsequent increase of intracranial pressure. A key molecule in these processes is the gas nitric oxide, which is produced in excess during neuroinflammation.

Ronopterin (VAS203) is an inhibitor of nitric oxide synthase. Ronopterin reduces excess nitric oxide production and subsequent secondary injury.

Eligibility criteria: Inclusion Criteria:

1. Written informed consent from patient's legal guardian or legal representative or deferred consent procedure, according to local requirements
2. 18 - 60 years of age, inclusive
3. Expected to survive more than 24 hours after admission
4. Traumatic Brain Injury (TBI) within the last 18 hours (infusion must not start earlier than 6 hours after the injury)
5. TBI with Glasgow Coma Score (GCS) ≥ 3 requiring intracranial pressure (ICP) monitoring according to the assessment of the treating physician.
6. Catheter placement (intraventricular or intraparenchymal, only) for monitoring and management of increased ICP
7. Systolic blood pressure ≥ 100 mmHg
8. Females of child-bearing potential must have a negative pregnancy test

Exclusion Criteria:

1. Penetrating head injury (e.g. missile, stab wound)
2. Concurrent, but not pre-existing, spinal cord injury
3. Bilateral fixed and dilated pupil (\> 4 mm)
4. Cardiopulmonary resuscitation performed post injury, or extracranial injuries causing continuing bleeding likely to require multiple transfusions (\> 4 units red blood cells)
5. Coma due to an exclusive epidural hematoma (lucid interval and absence of structural brain damage on CT scan)
6. Coma suspected to be primarily due to other causes than head injury (e.g. drug overdose intoxication, drowning/near drowning)
7. Known or CT scan evidence of pre-existing major cerebral damage
8. Patients who cannot be monitored with regard to their recovery (eGOS-I and QOLIBRI)
9. Patients and relatives of patients who don´t understand/speak Spanish, or English, or French, or German
10. Decompressive craniectomy, planned prior to randomisation
11. Polytraumatic patients with Injury Severity Score non-head \> 18
12. Rhabdomyolysis with Creatine Kinase \> 5000 IU/L
13. Injuries to ascending aorta and/or carotid arteries and vertebral arteries
14. Serum creatinine values \> 1.2 mg/dL (106 µmol/L) (women), or \> 1.5 mg/dL (133 µmol/L) (men)
15. Estimated glomerular filtration rate (eGFR) \< 60 mL/min as calculated by Chronic Kidney Disease Epidemiology Collaboration Formula
16. BMI \< 18.5 kg/m2 and \> 40 kg/m2, Body weight \> 110 kg
17. Any severe concomitant condition (cancer; hematologic, renal, hepatic, coronary disease; major psychiatric disorder; alcohol or drug abuse), that can be ascertained at admission
18. Known to have received an experimental drug within 4 weeks prior to current injury

Primary outcomes:
measure: extended Glasgow Outcome Scale
timeFrame: 6 months
Secondary outcomes:
measure: Quality of life after brain injury (QOLIBRI)
timeFrame: 6 months
measure: QOLIBRI overall scale
timeFrame: 6 months
measure: extended Glasgow Outcome Scale
timeFrame: 3 months
measure: QOLIBRI overall scale
timeFrame: 3 months
measure: Therapy Intensity Level
timeFrame: 14 days
measure: Number of decompressive craniectomies
timeFrame: 14 days
Other outcomes:
measure: Adverse Events
timeFrame: 14 days
measure: Renal function
timeFrame: 14 days
measure: Mortality
timeFrame: 6 Months
Locations:
city: Graz
country: Austria
facility: Universitätsklinik für Neurochirurgie
city: Innsbruck
country: Austria
facility: Neurologie und Neurochirurgie Medizinische Universität Innsbruck
city: Wien
country: Austria
facility: Klinik für Allgemeine Anästhesie und Intensivmedizin AKH Wien
city: Bordeaux
country: France
facility: Hôpital Pellegrin Service de réanimation traumatologique et chirurgicale
city: Clermont-Ferrand
country: France
facility: Hopital Gabriel Montpied
city: Nimes
country: France
facility: Pôle Anesthésie Réanimation Douleur Urgence
city: Toulon
country: France
facility: HIA Sainte-Anne Boulevard Sainte-Anne
city: Berlin
country: Germany
facility: Charite Virchow-Klinikum
city: Bochum
country: Germany
facility: Berufsgenossenschaftliche Kliniken Bergmannsheil Klinik für Neurochirurgie
city: Celle
country: Germany
facility: Allgemeines Krankenhaus Celle Neurotraumatologie
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf Neurochirurgische Klinik
city: Frankfurt
country: Germany
facility: Klinik für Neurochirurgie Universität Frankfurt
city: Göttingen
country: Germany
facility: Universitätsklinikum Göttingen Klinik für Neurochirurgie
city: Halle
country: Germany
facility: Berufsgenossenschaftliche Kliniken Bergmannstrost Halle Klinik für Neurochirurgie
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf Klinik und Poliklinik für Neurochirurgie
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover Klinik für Neurochirurgie
city: Heidelberg
country: Germany
facility: Neurochirurgische Universitätsklinik Heidelberg
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlands
city: Jena
country: Germany
facility: Universitätsklinikum Jena Klinik und Poliklinik für Neurochirurgie
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein Klinik für Neurochirurgie
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig Klinik und Poliklinik für Neurochirurgie
city: Barcelona
country: Spain
facility: Vall d'Hebron University Hospital Department of Neurosurgery
city: Elche
country: Spain
facility: Hospital General Universitario
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Palma
country: Spain
facility: Son Espases University Hospital
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital Birmingham
city: Edinburgh
country: United Kingdom
facility: NHS Lothian University of Edinburgh
city: London
country: United Kingdom
facility: Kings College Hospital London
city: Southampton
country: United Kingdom
facility: Southampton University Hospital Division of Clinical Neurosciences
Study officials:
affiliation: Medical University Innsbruck
name: Erich Schmutzhard, Prof. MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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. Epub 2014 Jul 28.
citation: 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, Fluh 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.