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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02794168
Recruitment Status : Recruiting
First Posted : June 8, 2016
Last Update Posted : December 17, 2018
ICON plc
Information provided by (Responsible Party):
Vasopharm 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.

Condition or disease Intervention/treatment Phase
Traumatic Brain Injury Drug: VAS203 Drug: Saline Phase 3

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  (Clinical Trial)
Estimated Enrollment : 220 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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 Start Date : June 2016
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : June 2019

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: VAS203 (Ronopterin)
Intravenous infusion of 17 mg/kg VAS203 over 48 hours, daily dose 8.5 mg/kg
Drug: VAS203
Other Name: Ronopterin

Placebo Comparator: Saline
Intravenous infusion of physiological saline over 48 hours
Drug: Saline

Primary Outcome Measures :
  1. extended Glasgow Outcome Scale [ Time Frame: 6 months ]
    clinical outcome questionnaire

Secondary Outcome Measures :
  1. Quality of life after brain injury (QOLIBRI) [ Time Frame: 6 months ]
    clinical outcome questionnaire

  2. QOLIBRI overall scale [ Time Frame: 6 months ]
    clinical outcome questionnaire

  3. extended Glasgow Outcome Scale [ Time Frame: 3 months ]
    clinical outcome questionnaire

  4. QOLIBRI overall scale [ Time Frame: 3 months ]
    clinical outcome questionnaire

  5. Therapy Intensity Level [ Time Frame: 14 days ]
    Daily recording of score for therapeutic measures

  6. Number of decompressive craniectomies [ Time Frame: 14 days ]
    Number of decompressive craniotomies on both hemispheres

Other Outcome Measures:
  1. Adverse Events [ Time Frame: 14 days ]
    Number of adverse events related to treatment

  2. Intracranial Pressure (ICP) and Cerebral Perfusion Pressure (CPP) [ Time Frame: 5 days ]
    Hourly recording of ICP and CPP

  3. Renal function [ Time Frame: 14 days ]
    Number of patients exhibiting acute kidney injury according Acute Kidney Injury Network criteria

  4. Mortality [ Time Frame: 6 Months ]
    Mortality 6 months after traumatic brain injury

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02794168

Contact: Reinhard Schinzel, PhD +49 931 359099 ext 115
Contact: Frank Tegtmeier, PhD +49 931 359099 ext 230

Universitätsklinik für Neurochirurgie Recruiting
Graz, Austria, 8036
Contact: Michael Mokry, Prof. Dr.         
Neurologie und Neurochirurgie Medizinische Universität Innsbruck Recruiting
Innsbruck, Austria
Contact: Ronny Beer, Prof. Dr.         
Klinik für Allgemeine Anästhesie und Intensivmedizin AKH Wien Recruiting
Wien, Austria
Contact: Harald Willschke, Prof. Dr.         
Hôpital Pellegrin Service de réanimation traumatologique et chirurgicale Recruiting
Bordeaux, France, 33076
Contact: Vincent Cottenceau, Dr.         
Hopital Gabriel Montpied Recruiting
Clermont-Ferrand, France, 63003
Contact: Russell Chabanne, Prof. Dr.         
Pôle Anesthésie Réanimation Douleur Urgence Recruiting
Nimes, France
Contact: Jean-Yves Lefrant, Prof. MD         
HIA Sainte-Anne Boulevard Sainte-Anne Recruiting
Toulon, France, 83800
Contact: Ambroise Montcriol, Dr.         
Unfallkrankenhaus Berlin - Neurochirurgie Recruiting
Berlin, Germany, 12683
Contact: Johannes Lemcke, PD Dr.         
Charite Virchow-Klinikum Recruiting
Berlin, Germany, 13353
Contact: Stefan Wolf, Dr.         
Berufsgenossenschaftliche Kliniken Bergmannsheil Klinik für Neurochirurgie Recruiting
Bochum, Germany
Contact: Ramon Martinez, PD Dr.         
Allgemeines Krankenhaus Celle Neurotraumatologie Recruiting
Celle, Germany
Contact: Eckhard Rickels, Prof. Dr.         
Universitätsklinikum Düsseldorf Neurochirurgische Klinik Recruiting
Düsseldorf, Germany
Contact: Karim Beseoglu, Dr.         
Klinik für Neurochirurgie Universität Frankfurt Recruiting
Frankfurt, Germany
Contact: Christian Senft, Prof. Dr.         
Universitätsklinikum Göttingen Klinik für Neurochirurgie Recruiting
Göttingen, Germany
Contact: Dorothea Mielke, Dr.         
Berufsgenossenschaftliche Kliniken Bergmannstrost Halle Klinik für Neurochirurgie Recruiting
Halle, Germany
Contact: Jörg Meisel, Prof. Dr.         
Universitätsklinikum Hamburg-Eppendorf Klinik und Poliklinik für Neurochirurgie Recruiting
Hamburg, Germany
Contact: Patrick Czorlich, Dr.         
Medizinische Hochschule Hannover Klinik für Neurochirurgie Recruiting
Hannover, Germany
Contact: Josef Lang, Dr.         
Neurochirurgische Universitätsklinik Heidelberg Recruiting
Heidelberg, Germany
Contact: Andreas Unterberg, Prof. Dr.         
Universitätsklinikum des Saarlands Recruiting
Homburg, Germany, 66421
Contact: Jacek Szczygielski, Dr.         
Universitätsklinikum Jena Klinik und Poliklinik für Neurochirurgie Recruiting
Jena, Germany
Contact: Jan Walter, Dr.         
Universitätsklinikum Schleswig-Holstein Klinik für Neurochirurgie Recruiting
Kiel, Germany
Contact: Michael Synowitz, Prof. Dr.         
Universitätsklinikum Leipzig Klinik und Poliklinik für Neurochirurgie Recruiting
Leipzig, Germany
Contact: Jürgen Meixensberger, Prof. Dr.         
Universitätsklinik Münster Recruiting
Münster, Germany, 48149
Contact: Markus Holling, PD Dr.         
Universitätsklinikum Würzburg Klinik und Poliklinik für Neurochirurgie Recruiting
Würzburg, Germany
Contact: Ralf-Ingo Ernestus, Prof. Dr.         
Vall d'Hebron University Hospital Department of Neurosurgery Recruiting
Barcelona, Spain, 08035
Contact: Juan Sahuquillo, Prof. Dr.         
Hospital General Universitario Recruiting
Elche, Spain
Contact: Perez Ana         
Son Espases University Hospital Recruiting
Palma, Spain
Contact: Javier Ibanez, MD PhD         
Hospital Clinico Universitario de Valencia Department of Anesthesiology and Critical Care Recruiting
Valencia, Spain, 46010
Contact: Rafael Badenes, MD PhD         
United Kingdom
Queen Elizabeth Hospital Birmingham Recruiting
Birmingham, United Kingdom
Contact: Antonio Belli, Prof. MD         
NHS Lothian University of Edinburgh Recruiting
Edinburgh, United Kingdom
Contact: Peter Andrew, Prof. MD         
Kings College Hospital London Recruiting
London, United Kingdom
Contact: Christos Tolias, PhD         
Southampton University Hospital Division of Clinical Neurosciences Recruiting
Southampton, United Kingdom
Contact: Diederik Bulters, Dr.         
Sponsors and Collaborators
Vasopharm GmbH
ICON plc
Principal Investigator: Erich Schmutzhard, Prof. MD Medical University Innsbruck

Responsible Party: Vasopharm GmbH Identifier: NCT02794168     History of Changes
Other Study ID Numbers: VAS203/III/1/04
First Posted: June 8, 2016    Key Record Dates
Last Update Posted: December 17, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Additional relevant MeSH terms:
Wounds and Injuries
Brain Injuries
Brain Injuries, Traumatic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System