Phase 2 a Study to Assess Safety and Pharmacokinetics of VAS203 in Patients With Traumatic Brain Injury

Traumatic Brain Injury Clinical Trial

— NOSTRA  

Official title:

An Exploratory Phase 2 a Study to Assess Safety, Tolerability, Pharmacodynamic and Pharmacokinetics of VAS203 in Patients With Moderate and Severe Traumatic Brain Injury

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02012582
• Other study ID #: VAS203/II/1/03
• Status: Completed
• Phase: Phase 2
• First received: December 10, 2013
• Last updated: February 8, 2016
• Start date: November 2009
• Est. completion date: September 2012

Study information

• Verified date: February 2016
• Source: Vasopharm GmbH
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Agencia Española de Medicamentos y Productos SanitariosFrance: Agence Nationale de Sécurité du Médicament et des produits de santéAustria: Austrian Medicines and Medical Devices AgencySwitzerland: Swissmedic
• Study type: Interventional

Clinical Trial Summary

In the exploratory multi-center Phase 2 a study safety, tolerability, pharmacodynamics and pharmacokinetics of the Nitric Oxide Synthase inhibitor VAS203 is assessed in patients with moderate and severe traumatic brain injury. Traumatic brain injury patients (32 males) receive 15, 20 and 30 mg/kg VAS203, respectively, by continuous infusion in three cohorts (Cohort 1 open; Cohorts 2 and 3 double blind, randomised placebo-controlled). End of Study for all patients will be Day 14; adverse events and concomitant medications will be documented throughout the study.

Objectives are to assess safety and tolerability of VAS203, to evaluate concentrations of metabolites of VAS203 in plasma and microdialysate and to assess pharmacodynamic effects of VAS203 on surrogate parameters. Safety parameter will include vital signs (blood pressure heart rate, respiration rate, oxygen saturation and blood gases), fluid balance, ECG, laboratory examinations (clinical chemistry, liver function, haematology/coagulation, urinalysis, renal parameters) and adverse events. Concentration of VAS203 will be determined in plasma and microdialysate. Pharmacodynamic parameters will include intracranial pressure (ICP), biochemical parameters in microdialysate (nitrite/nitrate, arginine, citrulline, pyruvate, lactate, glucose), Partial Oxygen Pressure in brain parenchyma and Therapy Intensity Level (TIL).

Description:

Intravenous administration of study medication for each patient will start as soon as possible but not later than 12 hours after trauma. Patients in Group 1 will receive open label study drug (VAS203). Patients in Group 2 and 3 will be randomised to treatment with VAS203 or placebo.

In addition to study treatment, each patient will receive the best "standard of care" for the study centre; no treatment will be withheld.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: September 2012
• Est. primary completion date: June 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Written informed consent from patient's legal guardian or legal representative

• 18 - 65 years of age, inclusive

• Head trauma within the last 12 hours

• Traumatic brain injury with Glasgow Coma Score (GCS) = 5 and that requires ICP monitoring

• Catheter placement for monitoring and management of increased ICP

• Microdialysis probe placement in penumbra zone or ipsilateral to contusion if focal

• 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)

• Not expected to survive more than 24 hours after admission

• Concurrent, but not pre-existing, spinal cord injury

• Unilateral and bilateral fixed and dilated pupil (> 4 mm)

• Cardiopulmonary resuscitation performed post injury

• continuing bleeding likely to require multiple transfusions (> 4 units red blood cells)

• Coma due to a "pure" 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)

• Known or CT scan evidence of pre-existing major cerebral damage

• Decompressive craniectomy, planned prior to randomization

• Polytraumatic patients with Injury Severity Score > 25, or rhabdomyolysis

• Injuries to ascending aorta and/or carotid arteries

• serum creatinine values > 1.5 mg/dL

• estimated Glomerular Filtration Rate < 60 ml/min (MDRD-formula)

• body mass index (BMI) > 35, Body weight > 120 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

• Administration of > 100 ml of contrast media containing iodine

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain Injuries
• Traumatic Brain Injury

Intervention

Drug:
• VAS203
i.v. infusion
• Saline
i.v. infusion

Locations

Country	Name	City	State
Austria	Medical University Innsbruck Department of Neurology	Innsbruck
France	HIA Sainte-Anne Boulevard Sainte-Anne	Toulon
Spain	Hospital Clinic University of Barcelona Surgical Intensive Care Unit	Barcelona
Spain	Vall d'Hebron University Hospital Department of Neurosurgery	Barcelona
Switzerland	University Hospital Zuerich Surgical Intensive Care	Zuerich
United Kingdom	Southampton University Hospital Division of Clinical Neurosciences	Southampton

Sponsors (1)

Lead Sponsor	Collaborator
Vasopharm GmbH

Countries where clinical trial is conducted

Austria,  France,  Spain,  Switzerland,  United Kingdom, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety and Tolerability of VAS203 in Patients With Moderate and Severe TBI	Tolerability (good, satisfactory, sufficient, poor) of VAS203 in patients with moderate and severe TBI, as judged by the investigators at day 14.; Safety outcome measure description see safety section	14 days	Yes
Secondary	Duration (Number of Time-points) of Intracranial Pressure (ICP) > 20 mmHg		Hourly from start of infusion to 144 hours	No
Secondary	Duration (Number of Hours) of Cerebral Perfusion Pressure (CPP) < 60 mmHg	Duration (number of hours) of cerebral perfusion pressure (CPP) < 60 mmHg calculated from ICP and mean arterial blood pressure (MAP): CPP = MAP - ICP)	Hourly from start of infusion to 144 hours	No
Secondary	Therapy Intensity Level Score	Therapy Intensity Level Score: Total Score calculated daily as the sum of all individual measures, range from 3 (good outcome) to 50 (worst outcome): Scores: 0-2 Head elevation 0-8 Sedation 0-1 Paralysis 1-3 Hyperventilation 0-2 Increased Oxygenation 1-3 Cooling 0-2 Osmotherapy 0-3 CSF Drainage 0-1 Red Blood Cell Transfusion 1-3 Cerebral perfusion pressure 0-1 Surgery for mass lesion 0/5/10 none/unilateral/bilateral Decompressive Craniectomy 0/10 Laparatomy to treat intracranial hypertension due to abdominal hypertension	Daily from day 1 to day 6	No