Conditions: Traumatic Brain Injury
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 32
Healthy volunteers: no

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.

Arms:
arm 1: Three 5 mg/kg/12-hours infusion with 12 hours break after each infusion. Total dose: 15 mg/kg arm 2: 10 mg/kg/24 hours, 48 hour continuous infusion. Total dose: 20 mg/kg arm 3: 10 mg/kg/24 hours, 72 hour continuous infusion. Total dose: 30 mg/kg arm 4: 0.9 % Sodium chloride infusion

Interventions: intervention 1: VAS203 intervention 2: Saline
Intervention descriptions: intervention 1: i.v. infusion intervention 2: i.v. infusion

Protocol document: