Efficacy of VAS203 (Ronopterin) in Patients With Moderate and Severe Traumatic Brain Injury

Traumatic Brain Injury Clinical Trial

— NOSTRA-III  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02794168
• Other study ID #: VAS203/III/1/04
• Status: Completed
• Phase: Phase 3
• Start date: June 2016
• Est. completion date: June 30, 2020

Study information

• Verified date: October 2021
• Source: Vasopharm GmbH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 224
• Est. completion date: June 30, 2020
• Est. primary completion date: June 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Brain Injuries
• Brain Injuries, Traumatic
• Traumatic Brain Injury
• Wounds and Injuries

Intervention

Drug:
• VAS203
Treatment
• Saline
Placebo

Locations

Country	Name	City	State
Austria	Universitätsklinik für Neurochirurgie	Graz
Austria	Neurologie und Neurochirurgie Medizinische Universität Innsbruck	Innsbruck
Austria	Klinik für Allgemeine Anästhesie und Intensivmedizin AKH Wien	Wien
France	Hôpital Pellegrin Service de réanimation traumatologique et chirurgicale	Bordeaux
France	Hopital Gabriel Montpied	Clermont-Ferrand
France	Pôle Anesthésie Réanimation Douleur Urgence	Nimes
France	HIA Sainte-Anne Boulevard Sainte-Anne	Toulon
Germany	Charite Virchow-Klinikum	Berlin
Germany	Berufsgenossenschaftliche Kliniken Bergmannsheil Klinik für Neurochirurgie	Bochum
Germany	Allgemeines Krankenhaus Celle Neurotraumatologie	Celle
Germany	Universitätsklinikum Düsseldorf Neurochirurgische Klinik	Düsseldorf
Germany	Klinik für Neurochirurgie Universität Frankfurt	Frankfurt
Germany	Universitätsklinikum Göttingen Klinik für Neurochirurgie	Göttingen
Germany	Berufsgenossenschaftliche Kliniken Bergmannstrost Halle Klinik für Neurochirurgie	Halle
Germany	Universitätsklinikum Hamburg-Eppendorf Klinik und Poliklinik für Neurochirurgie	Hamburg
Germany	Medizinische Hochschule Hannover Klinik für Neurochirurgie	Hannover
Germany	Neurochirurgische Universitätsklinik Heidelberg	Heidelberg
Germany	Universitätsklinikum des Saarlands	Homburg
Germany	Universitätsklinikum Jena Klinik und Poliklinik für Neurochirurgie	Jena
Germany	Universitätsklinikum Schleswig-Holstein Klinik für Neurochirurgie	Kiel
Germany	Universitätsklinikum Leipzig Klinik und Poliklinik für Neurochirurgie	Leipzig
Spain	Vall d'Hebron University Hospital Department of Neurosurgery	Barcelona
Spain	Hospital General Universitario	Elche
Spain	Hospital 12 de Octubre	Madrid
Spain	Son Espases University Hospital	Palma
United Kingdom	Queen Elizabeth Hospital Birmingham	Birmingham
United Kingdom	NHS Lothian University of Edinburgh	Edinburgh
United Kingdom	Kings College Hospital London	London
United Kingdom	Southampton University Hospital Division of Clinical Neurosciences	Southampton

Sponsors (2)

Lead Sponsor	Collaborator
Vasopharm GmbH	ICON plc

Countries where clinical trial is conducted

Austria,  France,  Germany,  Spain,  United Kingdom, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Adverse Events	Number of adverse events related to treatment	14 days
Other	Renal function	Number of patients exhibiting acute kidney injury according Acute Kidney Injury Network criteria	14 days
Other	Mortality	Mortality 6 months after traumatic brain injury	6 Months
Primary	extended Glasgow Outcome Scale	clinical outcome questionnaire	6 months
Secondary	Quality of life after brain injury (QOLIBRI)	clinical outcome questionnaire	6 months
Secondary	QOLIBRI overall scale	clinical outcome questionnaire	6 months
Secondary	extended Glasgow Outcome Scale	clinical outcome questionnaire	3 months
Secondary	QOLIBRI overall scale	clinical outcome questionnaire	3 months
Secondary	Therapy Intensity Level	Daily recording of score for therapeutic measures	14 days
Secondary	Number of decompressive craniectomies	Number of decompressive craniotomies on both hemispheres	14 days