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

Study Description

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Brief 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).

Condition or disease	Intervention/treatment	Phase
Traumatic Brain Injury	Drug: VAS203; Drug: Saline	Phase 2

Detailed 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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	32 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
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
Study Start Date :	November 2009
Actual Primary Completion Date :	June 2012
Actual Study Completion Date :	September 2012

Arms and Interventions

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Arm	Intervention/treatment
Experimental: VAS203 15 mg/kg; Three 5 mg/kg/12-hours infusion with 12 hours break after each infusion. Total dose: 15 mg/kg	Drug: VAS203; i.v. infusion; Other Name: Ronopterin
Experimental: VAS203 20 mg/kg; 10 mg/kg/24 hours, 48 hour continuous infusion. Total dose: 20 mg/kg	Drug: VAS203; i.v. infusion; Other Name: Ronopterin
Experimental: VAS203 30 mg/kg; 10 mg/kg/24 hours, 72 hour continuous infusion. Total dose: 30 mg/kg	Drug: VAS203; i.v. infusion; Other Name: Ronopterin
Placebo Comparator: Saline; 0.9 % Sodium chloride infusion	Drug: Saline; i.v. infusion; Other Name: 0.9 % NaCl

Outcome Measures

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Primary Outcome Measures :

1. Safety and Tolerability of VAS203 in Patients With Moderate and Severe TBI [ Time Frame: 14 days ]

   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

Secondary Outcome Measures :

1. Duration (Number of Time-points) of Intracranial Pressure (ICP) > 20 mmHg [ Time Frame: Hourly from start of infusion to 144 hours ]
2. Duration (Number of Hours) of Cerebral Perfusion Pressure (CPP) < 60 mmHg [ Time Frame: Hourly from start of infusion to 144 hours ]
   Duration (number of hours) of cerebral perfusion pressure (CPP) < 60 mmHg calculated from ICP and mean arterial blood pressure (MAP): CPP = MAP - ICP)
3. Therapy Intensity Level Score [ Time Frame: Daily from day 1 to day 6 ]

   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

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 65 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Locations

Austria
Medical University Innsbruck Department of Neurology
Innsbruck, Austria, 6020
France
HIA Sainte-Anne Boulevard Sainte-Anne
Toulon, France, 83800
Spain
Vall d'Hebron University Hospital Department of Neurosurgery
Barcelona, Spain, 08035
Hospital Clinic University of Barcelona Surgical Intensive Care Unit
Barcelona, Spain, 08036
Switzerland
University Hospital Zuerich Surgical Intensive Care
Zuerich, Switzerland, 8091
United Kingdom
Southampton University Hospital Division of Clinical Neurosciences
Southampton, United Kingdom, SO16 6YD

Sponsors and Collaborators

Vasopharm GmbH

Investigators

Study Director:	Frank Tegtmeier, Dr.	Vasopharm GmbH

More Information

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Publications of Results:

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.

Responsible Party:	Vasopharm GmbH
ClinicalTrials.gov Identifier:	NCT02012582 History of Changes
Other Study ID Numbers:	VAS203/II/1/03
First Posted:	December 16, 2013
Results First Posted:	March 7, 2016
Last Update Posted:	March 7, 2016
Last Verified:	February 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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