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

NCT ID: NCT02794168

Last Updated: 2021-10-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 224 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-06-30
• Study Completion Date: 2020-06-30

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.

Conditions

Traumatic Brain Injury

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

VAS203 (Ronopterin)

Intravenous infusion of 17 mg/kg VAS203 over 48 hours, daily dose 8.5 mg/kg

Group Type: EXPERIMENTAL

VAS203

Intervention Type: DRUG

Treatment

Saline

Intravenous infusion of physiological saline over 48 hours

Group Type: PLACEBO_COMPARATOR

Saline

Intervention Type: DRUG

Placebo

Interventions

VAS203

Treatment

Intervention Type: DRUG

Saline

Placebo

Intervention Type: DRUG

Other Intervention Names

Ronopterin

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

ICON plc

INDUSTRY

Sponsor Role: collaborator

veriNOS operations GmbH

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Erich Schmutzhard, Prof. MD

Role: PRINCIPAL_INVESTIGATOR

Medical University Innsbruck

Locations

Universitätsklinik für Neurochirurgie

Graz, , Austria

Neurologie und Neurochirurgie Medizinische Universität Innsbruck

Innsbruck, , Austria

Klinik für Allgemeine Anästhesie und Intensivmedizin AKH Wien

Vienna, , Austria

Hôpital Pellegrin Service de réanimation traumatologique et chirurgicale

Bordeaux, , France

Hopital Gabriel Montpied

Clermont-Ferrand, , France

Pôle Anesthésie Réanimation Douleur Urgence

Nîmes, , France

HIA Sainte-Anne Boulevard Sainte-Anne

Toulon, , France

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

Hanover, , 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, , Germany

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, , Spain

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, , United Kingdom

Countries

Austria; France; Germany; Spain; United Kingdom

References

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.

Reference Type: BACKGROUND

PMID: 24831445 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31937347 (View on PubMed)

Other Identifiers

VAS203/III/1/04

Identifier Type: -

Identifier Source: org_study_id