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

Study Overview
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Brief Summary
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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
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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.

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

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 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Quadruple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | 
| 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 |