Traumatic Brain Injury
Conditions
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.
Interventions
DRUGVAS203
i.v. infusion
DRUGSaline
i.v. infusion
Sponsors
veriNOS operations GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of VAS203 in Patients With Moderate and Severe TBI | 14 days | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Duration (number of hours) of cerebral perfusion pressure (CPP) \< 60 mmHg calculated from ICP and mean arterial blood pressure (MAP): CPP = MAP - ICP) |
| Therapy Intensity Level Score | Daily from day 1 to day 6 | 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 |
Countries
Austria, France, Spain, Switzerland, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| VAS203 15 mg/kg Three 5 mg/kg/12-hours infusion with 12 hours break after each infusion. Total dose: 15 mg/kg
VAS203 | 8 |
| VAS203 20 mg/kg 10 mg/kg/24 hours, 48 hour continuous infusion. Total dose: 20 mg/kg
VAS203 | 8 |
| VAS203 30 mg/kg 10 mg/kg/24 hours, 72 hour continuous infusion. Total dose: 30 mg/kg
VAS203 | 8 |
| Placebo 0.9 % Sodium chloride infusion
Saline | 8 |
| Total | 32 |
Baseline characteristics
| Characteristic | VAS203 15 mg/kg | VAS203 20 mg/kg | VAS203 30 mg/kg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 36.6 years | 34.8 years | 45.3 years | 35.9 years | 38.9 years |
| Region of Enrollment Austria | 0 participants | 0 participants | 1 participants | 1 participants | 2 participants |
| Region of Enrollment France | 1 participants | 1 participants | 1 participants | 2 participants | 5 participants |
| Region of Enrollment Spain | 4 participants | 2 participants | 3 participants | 4 participants | 13 participants |
| Region of Enrollment Switzerland | 1 participants | 5 participants | 2 participants | 1 participants | 9 participants |
| Region of Enrollment United Kingdom | 2 participants | 0 participants | 1 participants | 0 participants | 3 participants |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 1 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 8 Participants | 5 Participants | 7 Participants | 6 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 8 | 7 / 8 | 8 / 8 | 8 / 8 |
| serious Total, serious adverse events | 2 / 8 | 0 / 8 | 4 / 8 | 2 / 8 |
Outcome results
Primary
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
Time frame: 14 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| VAS203 15 mg/kg | Safety and Tolerability of VAS203 in Patients With Moderate and Severe TBI | Tolerability good | 8 participants |
| VAS203 15 mg/kg | Safety and Tolerability of VAS203 in Patients With Moderate and Severe TBI | Tolerability poor | 0 participants |
| VAS203 20 mg/kg | Safety and Tolerability of VAS203 in Patients With Moderate and Severe TBI | Tolerability poor | 0 participants |
| VAS203 20 mg/kg | Safety and Tolerability of VAS203 in Patients With Moderate and Severe TBI | Tolerability good | 8 participants |
| VAS203 30 mg/kg | Safety and Tolerability of VAS203 in Patients With Moderate and Severe TBI | Tolerability poor | 2 participants |
| VAS203 30 mg/kg | Safety and Tolerability of VAS203 in Patients With Moderate and Severe TBI | Tolerability good | 6 participants |
| Placebo | Safety and Tolerability of VAS203 in Patients With Moderate and Severe TBI | Tolerability good | 8 participants |
| Placebo | Safety and Tolerability of VAS203 in Patients With Moderate and Severe TBI | Tolerability poor | 0 participants |
Secondary
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)
Time frame: Hourly from start of infusion to 144 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VAS203 15 mg/kg | Duration (Number of Hours) of Cerebral Perfusion Pressure (CPP) < 60 mmHg | 16.5 hours | Standard Deviation 26.9 |
| VAS203 20 mg/kg | Duration (Number of Hours) of Cerebral Perfusion Pressure (CPP) < 60 mmHg | 5.9 hours | Standard Deviation 8 |
| VAS203 30 mg/kg | Duration (Number of Hours) of Cerebral Perfusion Pressure (CPP) < 60 mmHg | 11.8 hours | Standard Deviation 14.4 |
| Placebo | Duration (Number of Hours) of Cerebral Perfusion Pressure (CPP) < 60 mmHg | 9.4 hours | Standard Deviation 9.4 |
Secondary
Duration (Number of Time-points) of Intracranial Pressure (ICP) > 20 mmHg
Time frame: Hourly from start of infusion to 144 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VAS203 15 mg/kg | Duration (Number of Time-points) of Intracranial Pressure (ICP) > 20 mmHg | 9 hours | Standard Deviation 13.3 |
| VAS203 20 mg/kg | Duration (Number of Time-points) of Intracranial Pressure (ICP) > 20 mmHg | 9 hours | Standard Deviation 13.8 |
| VAS203 30 mg/kg | Duration (Number of Time-points) of Intracranial Pressure (ICP) > 20 mmHg | 12.9 hours | Standard Deviation 29.5 |
| Placebo | Duration (Number of Time-points) of Intracranial Pressure (ICP) > 20 mmHg | 12.8 hours | Standard Deviation 16.4 |
Secondary
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
Time frame: Daily from day 1 to day 6
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| VAS203 15 mg/kg | Therapy Intensity Level Score | Day 6 | 9 units on a scale | Standard Deviation 2.8 |
| VAS203 15 mg/kg | Therapy Intensity Level Score | Day 4 | 10.4 units on a scale | Standard Deviation 3.2 |
| VAS203 15 mg/kg | Therapy Intensity Level Score | Day 2 | 11.1 units on a scale | Standard Deviation 1.6 |
| VAS203 15 mg/kg | Therapy Intensity Level Score | Day 3 | 10.5 units on a scale | Standard Deviation 2 |
| VAS203 15 mg/kg | Therapy Intensity Level Score | Day 5 | 9.6 units on a scale | Standard Deviation 3.1 |
| VAS203 15 mg/kg | Therapy Intensity Level Score | Day 1 | 11.4 units on a scale | Standard Deviation 3.5 |
| VAS203 20 mg/kg | Therapy Intensity Level Score | Day 5 | 9.5 units on a scale | Standard Deviation 4.7 |
| VAS203 20 mg/kg | Therapy Intensity Level Score | Day 6 | 9.5 units on a scale | Standard Deviation 4.7 |
| VAS203 20 mg/kg | Therapy Intensity Level Score | Day 2 | 10.5 units on a scale | Standard Deviation 3.7 |
| VAS203 20 mg/kg | Therapy Intensity Level Score | Day 1 | 11.8 units on a scale | Standard Deviation 3.5 |
| VAS203 20 mg/kg | Therapy Intensity Level Score | Day 3 | 9.1 units on a scale | Standard Deviation 4.1 |
| VAS203 20 mg/kg | Therapy Intensity Level Score | Day 4 | 9.6 units on a scale | Standard Deviation 4.5 |
| VAS203 30 mg/kg | Therapy Intensity Level Score | Day 1 | 10 units on a scale | Standard Deviation 2.6 |
| VAS203 30 mg/kg | Therapy Intensity Level Score | Day 2 | 10.3 units on a scale | Standard Deviation 3.5 |
| VAS203 30 mg/kg | Therapy Intensity Level Score | Day 5 | 8.8 units on a scale | Standard Deviation 3.5 |
| VAS203 30 mg/kg | Therapy Intensity Level Score | Day 4 | 8.9 units on a scale | Standard Deviation 3.3 |
| VAS203 30 mg/kg | Therapy Intensity Level Score | Day 6 | 8.1 units on a scale | Standard Deviation 4.7 |
| VAS203 30 mg/kg | Therapy Intensity Level Score | Day 3 | 9.3 units on a scale | Standard Deviation 2.6 |
| Placebo | Therapy Intensity Level Score | Day 6 | 12 units on a scale | Standard Deviation 3.6 |
| Placebo | Therapy Intensity Level Score | Day 1 | 11.3 units on a scale | Standard Deviation 2.6 |
| Placebo | Therapy Intensity Level Score | Day 2 | 11.5 units on a scale | Standard Deviation 3.2 |
| Placebo | Therapy Intensity Level Score | Day 3 | 12.3 units on a scale | Standard Deviation 5.7 |
| Placebo | Therapy Intensity Level Score | Day 4 | 12.4 units on a scale | Standard Deviation 6.5 |
| Placebo | Therapy Intensity Level Score | Day 5 | 12.7 units on a scale | Standard Deviation 5.5 |
Comparison: Placebo versus pooled VAS203 Arms/Groupsp-value: <0.04Mixed Models Analysis
Post Hoc
Extended Glasgow Outcome Score (eGOS)
Scoring: Range from 1 (worst outcome) to 8 (good outcome). The patient´s overall rating is based on the lowest outcome category indicated on the scale. Score Description 1. Dead 2. Vegetative State 3. Lower Severe Disability 4. Upper Severe Disability 5. Lower Moderate Disability 6. Upper Moderate Disability 7. Lower Good Recovery 8. Upper Good Recovery
Time frame: 6 months after start of treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| VAS203 15 mg/kg | Extended Glasgow Outcome Score (eGOS) | 6.5 units on a scale |
| VAS203 20 mg/kg | Extended Glasgow Outcome Score (eGOS) | 7 units on a scale |
| VAS203 30 mg/kg | Extended Glasgow Outcome Score (eGOS) | 6 units on a scale |
| Placebo | Extended Glasgow Outcome Score (eGOS) | 4.5 units on a scale |
Comparison: Placebo versus pooled VAS203 Arms/Groupp-value: <0.01Kruskal-Wallis