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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Traumatic Brain Injury

Intervention / Treatment
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* Drug: VAS203
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent from patient's legal guardian or legal representative or deferred consent procedure, according to local requirements 18 - 60 years of age, inclusive Expected to survive more than 24 hours after admission Traumatic Brain Injury (TBI) within the last 18 hours (infusion must not start earlier than 6 hours after the injury) TBI with Glasgow Coma Score (GCS) ≥ 3 requiring intracranial pressure (ICP) monitoring according to the assessment of the treating physician. Catheter placement (intraventricular or intraparenchymal, only) for monitoring and management of increased ICP Systolic blood pressure ≥ 100 mmHg Females of child-bearing potential must have a negative pregnancy test Exclusion Criteria: Penetrating head injury (e.g. missile, stab wound) Concurrent, but not pre-existing, spinal cord injury Bilateral fixed and dilated pupil (> 4 mm) Cardiopulmonary resuscitation performed post injury, or extracranial injuries causing continuing bleeding likely to require multiple transfusions (> 4 units red blood cells) Coma due to an exclusive epidural hematoma (lucid interval and absence of structural brain damage on CT scan) Coma suspected to be primarily due to other causes than head injury (e.g. drug overdose intoxication, drowning/near drowning) Known or CT scan evidence of pre-existing major cerebral damage Patients who cannot be monitored with regard to their recovery (eGOS-I and QOLIBRI) Patients and relatives of patients who don´t understand/speak Spanish, or English, or French, or German Decompressive craniectomy, planned prior to randomisation Polytraumatic patients with Injury Severity Score non-head > 18 Rhabdomyolysis with Creatine Kinase > 5000 IU/L Injuries to ascending aorta and/or carotid arteries and vertebral arteries Serum creatinine values > 1.2 mg/dL (106 µmol/L) (women), or > 1.5 mg/dL (133 µmol/L) (men) Estimated glomerular filtration rate (eGFR) < 60 mL/min as calculated by Chronic Kidney Disease Epidemiology Collaboration Formula BMI < 18.5 kg/m2 and > 40 kg/m2, Body weight > 110 kg Any severe concomitant condition (cancer; hematologic, renal, hepatic, coronary disease; major psychiatric disorder; alcohol or drug abuse), that can be ascertained at admission Known to have received an experimental drug within 4 weeks prior to current injury

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VAS203 (Ronopterin)<br>Intravenous infusion of 17 mg/kg VAS203 over 48 hours, daily dose 8.5 mg/kg | Drug: VAS203<br>* Treatment<br>* Other names: Ronopterin;|
| Placebo Comparator: Saline<br>Intravenous infusion of physiological saline over 48 hours | Drug: Saline<br>* Placebo<br>|

What is the study measuring?
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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 |