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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. Read our disclaimer for details. Identifier: NCT02794168
Recruitment Status : Completed
First Posted : June 8, 2016
Last Update Posted : September 22, 2020
ICON plc
Information provided by (Responsible Party):
Vasopharm GmbH

Tracking Information
First Submitted Date  ICMJE May 31, 2016
First Posted Date  ICMJE June 8, 2016
Last Update Posted Date September 22, 2020
Actual Study Start Date  ICMJE June 2016
Actual Primary Completion Date June 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 7, 2016)
extended Glasgow Outcome Scale [ Time Frame: 6 months ]
clinical outcome questionnaire
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 7, 2016)
  • Quality of life after brain injury (QOLIBRI) [ Time Frame: 6 months ]
    clinical outcome questionnaire
  • QOLIBRI overall scale [ Time Frame: 6 months ]
    clinical outcome questionnaire
  • extended Glasgow Outcome Scale [ Time Frame: 3 months ]
    clinical outcome questionnaire
  • QOLIBRI overall scale [ Time Frame: 3 months ]
    clinical outcome questionnaire
  • Therapy Intensity Level [ Time Frame: 14 days ]
    Daily recording of score for therapeutic measures
  • Number of decompressive craniectomies [ Time Frame: 14 days ]
    Number of decompressive craniotomies on both hemispheres
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: June 7, 2016)
  • Adverse Events [ Time Frame: 14 days ]
    Number of adverse events related to treatment
  • Intracranial Pressure (ICP) and Cerebral Perfusion Pressure (CPP) [ Time Frame: 5 days ]
    Hourly recording of ICP and CPP
  • Renal function [ Time Frame: 14 days ]
    Number of patients exhibiting acute kidney injury according Acute Kidney Injury Network criteria
  • Mortality [ Time Frame: 6 Months ]
    Mortality 6 months after traumatic brain injury
Original Other Pre-specified Outcome Measures Same as current
Descriptive Information
Brief Title  ICMJE Efficacy of VAS203 (Ronopterin) in Patients With Moderate and Severe Traumatic Brain Injury
Official Title  ICMJE 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
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Traumatic Brain Injury
Intervention  ICMJE
  • Drug: VAS203
    Other Name: Ronopterin
  • Drug: Saline
Study Arms  ICMJE
  • Experimental: VAS203 (Ronopterin)
    Intravenous infusion of 17 mg/kg VAS203 over 48 hours, daily dose 8.5 mg/kg
    Intervention: Drug: VAS203
  • Placebo Comparator: Saline
    Intravenous infusion of physiological saline over 48 hours
    Intervention: Drug: Saline
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 15, 2020)
Original Estimated Enrollment  ICMJE
 (submitted: June 7, 2016)
Actual Study Completion Date  ICMJE June 30, 2020
Actual Primary Completion Date June 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   France,   Germany,   Spain,   United Kingdom
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT02794168
Other Study ID Numbers  ICMJE VAS203/III/1/04
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Vasopharm GmbH
Study Sponsor  ICMJE Vasopharm GmbH
Collaborators  ICMJE ICON plc
Investigators  ICMJE
Principal Investigator: Erich Schmutzhard, Prof. MD Medical University Innsbruck
PRS Account Vasopharm GmbH
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP