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

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

Sponsors

Lead Sponsor: Vasopharm GmbH

Source Vasopharm 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.

Overall Status Completed
Start Date November 2009
Completion Date September 2012
Primary Completion Date June 2012
Phase Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Safety and Tolerability of VAS203 in Patients With Moderate and Severe TBI 14 days
Secondary Outcome
Measure 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 Hourly from start of infusion to 144 hours
Therapy Intensity Level Score Daily from day 1 to day 6
Enrollment 32
Condition
Intervention

Intervention Type: Drug

Intervention Name: VAS203

Description: i.v. infusion

Other Name: Ronopterin

Intervention Type: Drug

Intervention Name: Saline

Description: i.v. infusion

Arm Group Label: Saline

Other Name: 0.9 % NaCl

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

Gender: All

Minimum Age: 18 Years

Maximum Age: 65 Years

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Frank Tegtmeier, Dr. Study Director Vasopharm GmbH
Location
Facility:
Medical University Innsbruck Department of Neurology | Innsbruck, 6020, Austria
HIA Sainte-Anne Boulevard Sainte-Anne | Toulon, 83800, France
Vall d'Hebron University Hospital Department of Neurosurgery | Barcelona, 08035, Spain
Hospital Clinic University of Barcelona Surgical Intensive Care Unit | Barcelona, 08036, Spain
University Hospital Zuerich Surgical Intensive Care | Zuerich, 8091, Switzerland
Southampton University Hospital Division of Clinical Neurosciences | Southampton, SO16 6YD, United Kingdom
Location Countries

Austria

France

Spain

Switzerland

United Kingdom

Verification Date

February 2016

Responsible Party

Type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 4
Arm Group

Label: VAS203 15 mg/kg

Type: Experimental

Description: Three 5 mg/kg/12-hours infusion with 12 hours break after each infusion. Total dose: 15 mg/kg

Label: VAS203 20 mg/kg

Type: Experimental

Description: 10 mg/kg/24 hours, 48 hour continuous infusion. Total dose: 20 mg/kg

Label: VAS203 30 mg/kg

Type: Experimental

Description: 10 mg/kg/24 hours, 72 hour continuous infusion. Total dose: 30 mg/kg

Label: Saline

Type: Placebo Comparator

Description: 0.9 % Sodium chloride infusion

Acronym NOSTRA
Patient Data No
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Source: ClinicalTrials.gov