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

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

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.

Study Overview

• Status: Completed
• Conditions: Traumatic Brain Injury
• Intervention / Treatment: Drug: Saline; Drug: VAS203

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 Type: Interventional
• Enrollment (Actual): 224
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8036
    • Universitätsklinik für Neurochirurgie
  • Innsbruck, Austria
    • Neurologie und Neurochirurgie Medizinische Universität Innsbruck
  • Wien, Austria
    • Klinik für Allgemeine Anästhesie und Intensivmedizin AKH Wien
• France
  • Bordeaux, France, 33076
    • Hôpital Pellegrin Service de réanimation traumatologique et chirurgicale
  • Clermont-Ferrand, France, 63003
    • Hopital Gabriel Montpied
  • Nimes, France
    • Pôle Anesthésie Réanimation Douleur Urgence
  • Toulon, France, 83800
    • HIA Sainte-Anne Boulevard Sainte-Anne
• Germany
  • Berlin, Germany, 13353
    • Charite Virchow-Klinikum
  • Bochum, Germany
    • Berufsgenossenschaftliche Kliniken Bergmannsheil Klinik für Neurochirurgie
  • Celle, Germany
    • Allgemeines Krankenhaus Celle Neurotraumatologie
  • Düsseldorf, Germany
    • Universitätsklinikum Düsseldorf Neurochirurgische Klinik
  • Frankfurt, Germany
    • Klinik für Neurochirurgie Universität Frankfurt
  • Göttingen, Germany
    • Universitätsklinikum Göttingen Klinik für Neurochirurgie
  • Halle, Germany
    • Berufsgenossenschaftliche Kliniken Bergmannstrost Halle Klinik für Neurochirurgie
  • Hamburg, Germany
    • Universitätsklinikum Hamburg-Eppendorf Klinik und Poliklinik für Neurochirurgie
  • Hannover, Germany
    • Medizinische Hochschule Hannover Klinik für Neurochirurgie
  • Heidelberg, Germany
    • Neurochirurgische Universitätsklinik Heidelberg
  • Homburg, Germany, 66421
    • Universitätsklinikum des Saarlands
  • Jena, Germany
    • Universitätsklinikum Jena Klinik und Poliklinik für Neurochirurgie
  • Kiel, Germany
    • Universitätsklinikum Schleswig-Holstein Klinik für Neurochirurgie
  • Leipzig, Germany
    • Universitätsklinikum Leipzig Klinik und Poliklinik für Neurochirurgie
• Spain
  • Barcelona, Spain, 08035
    • Vall d'Hebron University Hospital Department of Neurosurgery
  • Elche, Spain
    • Hospital General Universitario
  • Madrid, Spain
    • Hospital 12 de Octubre
  • Palma, Spain
    • Son Espases University Hospital
• United Kingdom
  • Birmingham, United Kingdom
    • Queen Elizabeth Hospital Birmingham
  • Edinburgh, United Kingdom
    • NHS Lothian University of Edinburgh
  • London, United Kingdom
    • Kings College Hospital London
  • Southampton, United Kingdom
    • Southampton University Hospital Division of Clinical Neurosciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: VAS203 (Ronopterin); Intravenous infusion of 17 mg/kg VAS203 over 48 hours, daily dose 8.5 mg/kg	Drug: VAS203; Treatment; Other Names: Ronopterin
PLACEBO_COMPARATOR: Saline; Intravenous infusion of physiological saline over 48 hours	Drug: Saline; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
extended Glasgow Outcome Scale	clinical outcome questionnaire	6 months

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	Number of adverse events related to treatment	14 days
Renal function	Number of patients exhibiting acute kidney injury according Acute Kidney Injury Network criteria	14 days
Mortality	Mortality 6 months after traumatic brain injury	6 Months

Collaborators and Investigators

• Sponsor: Vasopharm GmbH
• Collaborators: ICON plc
• Investigators: Principal Investigator: Erich Schmutzhard, Prof. MD, Medical University Innsbruck

Publications and helpful links

General Publications

• 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.
• 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. Erratum In: Trials. 2020 Feb 12;21(1):172.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 1, 2016
• Primary Completion (ACTUAL): June 30, 2020
• Study Completion (ACTUAL): June 30, 2020

Study Registration Dates

• First Submitted: May 31, 2016
• First Submitted That Met QC Criteria: June 7, 2016
• First Posted (ESTIMATE): June 8, 2016

Study Record Updates

• Last Update Posted (ACTUAL): October 11, 2021
• Last Update Submitted That Met QC Criteria: October 6, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic
• Other Study ID Numbers: VAS203/III/1/04

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED