An Exploratory Phase 2 a Study to Assess Safety, Tolerability, Pharmacodynamic and Pharmacokinetics of VAS203 in Patients With Moderate and Severe Traumatic Brain Injury
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 32
- 试验地点
- 6
- 主要终点
- Safety and Tolerability of VAS203 in Patients With Moderate and Severe TBI
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
VAS203 15 mg/kg
Three 5 mg/kg/12-hours infusion with 12 hours break after each infusion. Total dose: 15 mg/kg
干预措施: VAS203 (Drug)
VAS203 20 mg/kg
10 mg/kg/24 hours, 48 hour continuous infusion. Total dose: 20 mg/kg
干预措施: VAS203 (Drug)
VAS203 30 mg/kg
10 mg/kg/24 hours, 72 hour continuous infusion. Total dose: 30 mg/kg
干预措施: VAS203 (Drug)
Saline
0.9 % Sodium chloride infusion
干预措施: Saline (Drug)
结局指标
主要结局
Safety and Tolerability of VAS203 in Patients With Moderate and Severe TBI
时间窗: 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
次要结局
- 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)