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

NCT02012582 | Completed Phase 2 Results DMC

• 1 other identifier: VAS203/II/1/03
• Study Type: interventional
• Target: 32
• Locations: 5 countries
• Sites: 6

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).

Conditions

Traumatic Brain Injury

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• 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

Study Arms (4)

VAS203 15 mg/kg

EXPERIMENTAL

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

Drug: VAS203

VAS203 20 mg/kg

EXPERIMENTAL

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

Drug: VAS203

VAS203 30 mg/kg

EXPERIMENTAL

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

Drug: VAS203

Saline

PLACEBO COMPARATOR

0.9 % Sodium chloride infusion

Drug: Saline

Interventions

VAS203 DRUG

i.v. infusion

Also known as: Ronopterin

VAS203 15 mg/kg; VAS203 20 mg/kg; VAS203 30 mg/kg

Saline DRUG

i.v. infusion

Also known as: 0.9 % NaCl

Saline

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent from patient's legal guardian or legal representative
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• veriNOS operations GmbH: lead

Study Sites (6)

Medical University Innsbruck Department of Neurology

Innsbruck, 6020, Austria

Location

HIA Sainte-Anne Boulevard Sainte-Anne

Toulon, 83800, France

Location

Vall d'Hebron University Hospital Department of Neurosurgery

Barcelona, 08035, Spain

Location

Hospital Clinic University of Barcelona Surgical Intensive Care Unit

Barcelona, 08036, Spain

Location

University Hospital Zuerich Surgical Intensive Care

Zurich, 8091, Switzerland

Location

Southampton University Hospital Division of Clinical Neurosciences

Southampton, SO16 6YD, United Kingdom

Location

Related Publications (1)

• Stover JF, Belli A, Boret H, Bulters D, Sahuquillo J, Schmutzhard E, Zavala E, Ungerstedt U, Schinzel R, Tegtmeier F; NOSTRA Investigators. Nitric oxide synthase inhibition with the antipterin VAS203 improves outcome in moderate and severe traumatic brain injury: a placebo-controlled randomized Phase IIa trial (NOSTRA). J Neurotrauma. 2014 Oct 1;31(19):1599-606. doi: 10.1089/neu.2014.3344. Epub 2014 Jul 28.

  PMID: 24831445 RESULT

MeSH Terms

Conditions

Brain Injuries, Traumatic

Interventions

4-amino-tetrahydrobiopterin; Sodium Chloride

Condition Hierarchy (Ancestors)

Brain Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Results Point of Contact

• Title: Dr. Reinhard Schinzel
• Organization: vasopharm GmbH

schinzel@vasopharm.de

+49 931 359099

Study Officials

• Frank Tegtmeier, Dr.

  veriNOS operations GmbH

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 10, 2013
• First Posted: December 16, 2013
• Study Start: November 1, 2009
• Primary Completion: June 1, 2012
• Study Completion: September 1, 2012
• Last Updated: March 7, 2016
• Results First Posted: March 7, 2016

Record last verified: 2016-02

Data Sharing

• IPD Sharing: Will not share

Locations

ES (2); AU (1); FR (1); CH (1); GB (1)