Phase 2 a Study to Assess Safety and Pharmacokinetics of VAS203 in Patients With Traumatic Brain Injury (NOSTRA)
An Exploratory Phase 2 a Study to Assess Safety, Tolerability, Pharmacodynamic and Pharmacokinetics of VAS203 in Patients With Moderate and Severe Traumatic Brain Injury
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).
Visão geral do estudo
Status
Condições
Intervenção / Tratamento
Descrição detalhada
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.
Tipo de estudo
Inscrição (Real)
Estágio
- Fase 2
Contactos e Locais
Locais de estudo
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Barcelona, Espanha, 08035
- Vall d'Hebron University Hospital Department of Neurosurgery
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Barcelona, Espanha, 08036
- Hospital Clinic University of Barcelona Surgical Intensive Care Unit
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Toulon, França, 83800
- HIA Sainte-Anne Boulevard Sainte-Anne
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Southampton, Reino Unido, SO16 6YD
- Southampton University Hospital Division of Clinical Neurosciences
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Zuerich, Suíça, 8091
- University Hospital Zuerich Surgical Intensive Care
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Innsbruck, Áustria, 6020
- Medical University Innsbruck Department of Neurology
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Critérios de participação
Critérios de elegibilidade
Idades elegíveis para estudo
Aceita Voluntários Saudáveis
Gêneros Elegíveis para o Estudo
Descrição
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
Plano de estudo
Como o estudo é projetado?
Detalhes do projeto
- Finalidade Principal: Tratamento
- Alocação: Randomizado
- Modelo Intervencional: Atribuição Paralela
- Mascaramento: Quadruplicar
Armas e Intervenções
Grupo de Participantes / Braço |
Intervenção / Tratamento |
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Experimental: VAS203 15 mg/kg
Three 5 mg/kg/12-hours infusion with 12 hours break after each infusion.
Total dose: 15 mg/kg
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i.v. infusion
Outros nomes:
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Experimental: VAS203 20 mg/kg
10 mg/kg/24 hours, 48 hour continuous infusion.
Total dose: 20 mg/kg
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i.v. infusion
Outros nomes:
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Experimental: VAS203 30 mg/kg
10 mg/kg/24 hours, 72 hour continuous infusion.
Total dose: 30 mg/kg
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i.v. infusion
Outros nomes:
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Comparador de Placebo: Saline
0.9 % Sodium chloride infusion
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i.v. infusion
Outros nomes:
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O que o estudo está medindo?
Medidas de resultados primários
Medida de resultado |
Descrição da medida |
Prazo |
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Safety and Tolerability of VAS203 in Patients With Moderate and Severe TBI
Prazo: 14 days
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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
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Medidas de resultados secundários
Medida de resultado |
Descrição da medida |
Prazo |
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Duration (Number of Time-points) of Intracranial Pressure (ICP) > 20 mmHg
Prazo: Hourly from start of infusion to 144 hours
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Hourly from start of infusion to 144 hours
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Duration (Number of Hours) of Cerebral Perfusion Pressure (CPP) < 60 mmHg
Prazo: Hourly from start of infusion to 144 hours
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Duration (number of hours) of cerebral perfusion pressure (CPP) < 60 mmHg calculated from ICP and mean arterial blood pressure (MAP): CPP = MAP - ICP)
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Hourly from start of infusion to 144 hours
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Therapy Intensity Level Score
Prazo: Daily from day 1 to day 6
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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 |
Daily from day 1 to day 6
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Colaboradores e Investigadores
Patrocinador
Investigadores
- Diretor de estudo: Frank Tegtmeier, Dr., Vasopharm GmbH
Publicações e links úteis
Datas de registro do estudo
Datas Principais do Estudo
Início do estudo
Conclusão Primária (Real)
Conclusão do estudo (Real)
Datas de inscrição no estudo
Enviado pela primeira vez
Enviado pela primeira vez que atendeu aos critérios de CQ
Primeira postagem (Estimativa)
Atualizações de registro de estudo
Última Atualização Postada (Estimativa)
Última atualização enviada que atendeu aos critérios de controle de qualidade
Última verificação
Mais Informações
Termos relacionados a este estudo
Termos MeSH relevantes adicionais
Outros números de identificação do estudo
- VAS203/II/1/03
Plano para dados de participantes individuais (IPD)
Planeja compartilhar dados de participantes individuais (IPD)?
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Ensaios clínicos em Traumatismo crâniano
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University of Dublin, Trinity CollegeDesconhecidoAtletas de elite aposentados da Brain Health
Ensaios clínicos em VAS203
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Vasopharm GmbHICON plcConcluídoTraumatismo crânianoReino Unido, Espanha, França, Áustria, Alemanha
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Vasopharm GmbHWinicker Norimed GmbHConcluídoComprometimento da Função Renal em Voluntários SaudáveisAlemanha