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

Phase 3

Completed

• Conditions: Traumatic Brain Injury
• Interventions: Drug: VAS203; Drug: Saline

• Registration Number: NCT02794168
• Lead Sponsor: veriNOS operations GmbH

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.

Study Timeline

• Study First Submitted: 2016-05-31
• Study Start: 2016-06
• Study First Submitted QC: 2016-06-07
• Study First Posted: 2016-06-08
• Primary Completion: 2020-06-30
• Study Completion: 2020-06-30
• Status Verified: 2021-10
• Last Update Submitted: 2021-10-06
• Last Update Posted: 2021-10-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 224

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
VAS203 (Ronopterin)	VAS203	Intravenous infusion of 17 mg/kg VAS203 over 48 hours, daily dose 8.5 mg/kg
Saline	Saline	Intravenous infusion of physiological saline over 48 hours

Primary Outcome Measures

Name	Time	Method
extended Glasgow Outcome Scale	6 months	clinical outcome questionnaire

Secondary Outcome Measures

Name	Time	Method
Number of decompressive craniectomies	14 days	Number of decompressive craniotomies on both hemispheres
Quality of life after brain injury (QOLIBRI)	6 months	clinical outcome questionnaire
QOLIBRI overall scale	3 months	clinical outcome questionnaire
extended Glasgow Outcome Scale	3 months	clinical outcome questionnaire
Therapy Intensity Level	14 days	Daily recording of score for therapeutic measures

Trial Locations

Locations (29)

Hôpital Pellegrin Service de réanimation traumatologique et chirurgicale; 🇫🇷 Bordeaux, France

Pôle Anesthésie Réanimation Douleur Urgence; 🇫🇷 Nimes, France

Hopital Gabriel Montpied; 🇫🇷 Clermont-Ferrand, 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

Neurochirurgische Universitätsklinik Heidelberg; 🇩🇪 Heidelberg, Germany

Universitätsklinikum Hamburg-Eppendorf Klinik und Poliklinik für Neurochirurgie; 🇩🇪 Hamburg, Germany

Medizinische Hochschule Hannover Klinik für Neurochirurgie; 🇩🇪 Hannover, Germany

Universitätsklinikum Jena Klinik und Poliklinik für Neurochirurgie; 🇩🇪 Jena, Germany

Universitätsklinikum des Saarlands; 🇩🇪 Homburg, 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

Queen Elizabeth Hospital Birmingham; 🇬🇧 Birmingham, United Kingdom

Son Espases University Hospital; 🇪🇸 Palma, Spain

NHS Lothian University of Edinburgh; 🇬🇧 Edinburgh, United Kingdom

Southampton University Hospital Division of Clinical Neurosciences; 🇬🇧 Southampton, United Kingdom

Kings College Hospital London; 🇬🇧 London, United Kingdom

Universitätsklinik für Neurochirurgie; 🇦🇹 Graz, Austria

Klinik für Allgemeine Anästhesie und Intensivmedizin AKH Wien; 🇦🇹 Wien, Austria

Neurologie und Neurochirurgie Medizinische Universität Innsbruck; 🇦🇹 Innsbruck, Austria

Universitätsklinikum Schleswig-Holstein Klinik für Neurochirurgie; 🇩🇪 Kiel, Germany