Phase 2 a Study to Assess Safety and Pharmacokinetics of VAS203 in Patients With Traumatic Brain Injury
Condition: Traumatic Brain Injury
MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Wounds and Injuries
Intervention: VAS203; Saline
Intervention description: i.v. infusion; i.v. infusion
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No

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).
    

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