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

Phase 2

Completed

• Conditions: Traumatic Brain Injury
• Interventions: Drug: VAS203; Drug: Saline

• Registration Number: NCT02012582
• Lead Sponsor: veriNOS operations GmbH

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.

Study Timeline

• Study Start: 2009-11
• Primary Completion: 2012-06
• Study Completion: 2012-09
• Study First Submitted: 2013-12-10
• Study First Submitted QC: 2013-12-13
• Study First Posted: 2013-12-16
• Results First Submitted: 2015-12-29
• Status Verified: 2016-02
• Results First Submitted QC: 2016-02-08
• Last Update Submitted: 2016-02-08
• Results First Posted: 2016-03-07
• Last Update Posted: 2016-03-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 32

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
VAS203 15 mg/kg	VAS203	Three 5 mg/kg/12-hours infusion with 12 hours break after each infusion. Total dose: 15 mg/kg
VAS203 30 mg/kg	VAS203	10 mg/kg/24 hours, 72 hour continuous infusion. Total dose: 30 mg/kg
Saline	Saline	0.9 % Sodium chloride infusion
VAS203 20 mg/kg	VAS203	10 mg/kg/24 hours, 48 hour continuous infusion. Total dose: 20 mg/kg

Primary Outcome Measures

Name	Time	Method
Safety and Tolerability of VAS203 in Patients With Moderate and Severe TBI	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

Name	Time	Method
Duration (Number of Time-points) of Intracranial Pressure (ICP) > 20 mmHg	Hourly from start of infusion to 144 hours
Duration (Number of Hours) of Cerebral Perfusion Pressure (CPP) < 60 mmHg	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)
Therapy Intensity Level Score	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

Trial Locations

Locations (6)

Medical University Innsbruck Department of Neurology; 🇦🇹 Innsbruck, Austria

HIA Sainte-Anne Boulevard Sainte-Anne; 🇫🇷 Toulon, France

Vall d'Hebron University Hospital Department of Neurosurgery; 🇪🇸 Barcelona, Spain

Hospital Clinic University of Barcelona Surgical Intensive Care Unit; 🇪🇸 Barcelona, Spain

University Hospital Zuerich Surgical Intensive Care; 🇨🇭 Zuerich, Switzerland

Southampton University Hospital Division of Clinical Neurosciences; 🇬🇧 Southampton, United Kingdom