Clinical trial NCT02012582: Phase 2 a Study to Assess Safety and Pharmacokinetics of VAS203 in Patients With Traumatic Brain Injury
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Traumatic Brain Injury
Lead sponsor: veriNOS operations GmbH
Sponsor class: INDUSTRY
First posted: 2013-12-16
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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.

Eligibility 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

Primary outcomes:
measure: Safety and Tolerability of VAS203 in Patients With Moderate and Severe TBI
timeFrame: 14 days
Secondary outcomes:
measure: Duration (Number of Time-points) of Intracranial Pressure (ICP) > 20 mmHg
timeFrame: Hourly from start of infusion to 144 hours
measure: Duration (Number of Hours) of Cerebral Perfusion Pressure (CPP) < 60 mmHg
timeFrame: Hourly from start of infusion to 144 hours
measure: Therapy Intensity Level Score
timeFrame: Daily from day 1 to day 6
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Medical University Innsbruck Department of Neurology
city: Toulon
country: France
facility: HIA Sainte-Anne Boulevard Sainte-Anne
city: Barcelona
country: Spain
facility: Vall d'Hebron University Hospital Department of Neurosurgery
city: Barcelona
country: Spain
facility: Hospital Clinic University of Barcelona Surgical Intensive Care Unit
city: Zuerich
country: Switzerland
facility: University Hospital Zuerich Surgical Intensive Care
city: Southampton
country: United Kingdom
facility: Southampton University Hospital Division of Clinical Neurosciences
Study officials:
affiliation: veriNOS operations GmbH
name: Frank Tegtmeier, Dr.
role: STUDY_DIRECTOR
References:
citation: 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.