Overcoming Membrane Transporters to Improve CNS Drug Delivery - Improving Brain Antioxidants After Traumatic Brain Injury (Pro-NAC)
Overcoming Membrane Transporters to Improve CNS Drug Delivery
The overall purpose of this research study is to investigate the safety of pharmacological therapies that may potentially improve pediatric outcomes after traumatic brain injury. Traumatic brain injuries are the leading cause of death and disability among children and young adults.
Hypothesis: Combinational therapy with a membrane transporter and antioxidant are safe after TBI and can overcome barriers to the brain and synergistically improve bioavailability and efficacy the antioxidant content of the body and CNS after TBI.
Descripción general del estudio
Estado
Condiciones
Intervención / Tratamiento
Descripción detallada
Specific Aim: Define the capacity of the combination of probenecid and NAC to safely and synergistically preserve levels of GSH and reduce oxidative stress in children with severe TBI. We will enroll 20 children age 2 to less than 18 years old (less than 216 months) after severe TBI in a randomized, controlled study of administration of the combinational therapy and test if the administration of these drugs is safe and if antioxidant reserve can be preserved within the serum and CSF.
Probenecid (at the same dose that is used as an adjunct to antibiotic therapy) and NAC (at the same dose that is used for acetaminophen-induced liver disease), or vehicles will be given for 3 days. The primary outcomes of the study will be the safety of drug administration and the CSF and serum levels anti-oxidant reserve (AOR), with the presumption that maintaining anti-oxidant levels within the brain may prove neuroprotective. Other secondary outcomes (CSF and serum probenecid, NAC, GSH and phenytoin concentrations) will also be tested. Adverse events occuring during treatment with these drugs after TBI will be monitored by a local Data Safety Monitoring Board.
Tipo de estudio
Inscripción (Actual)
Fase
- Fase 2
- Fase 1
Contactos y Ubicaciones
Ubicaciones de estudio
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Pennsylvania
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Pittsburgh, Pennsylvania, Estados Unidos, 15213
- Children's Hospital of Pittsburgh of UPMC
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
Inclusion Criteria:
- Children (age 2 - 18 y) with severe TBI (GCS < or = 8) with an externalized ventricular drain placed for measurement of intracranial pressure
Exclusion Criteria:
- Brain dead on admission to ICU
- Pregnancy
- Contraindications to enteral medications
Contraindications to probenecid:
- status epilepticus
- blood dyscrasias
- under 2 years-of-age
- coadministration of salicylates
- renal dysfunction or urate kidney stones
- hypersensitivity to probenecid
- Contraindications to N-acetylcysteine: hypersensitivity to N-acetylcysteine
- Family unwilling to consent
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: Aleatorizado
- Modelo Intervencionista: Asignación paralela
- Enmascaramiento: Cuadruplicar
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
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Experimental: Drug
Probenecid and N-acetyl cysteine will be administered at standard doses for the first 4 days after TBI.
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After obtaining written parental consent, patients will be randomized by the use of a blind envelope system to one of the following: to receive probenecid (initial: 25 mg/kg/dose; maintenance: 10mg/kg/dose 4 x per day for 11 doses) and NAC (initial: 140mg/kg/dose; maintenance: 70mg/kg/dose 6 x per day for 17 doses) or the placebo via nasogastric (NG) or orogastric (OG) tube for 3 days or to receive placebos.
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Comparador de placebos: Placebo
Placebos will be prepared for the two experimental drugs and administered at identical time periods.
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After obtaining written parental consent, patients will be randomized by the use of a blind envelope system to one of the following: to receive probenecid (initial: 25 mg/kg/dose; maintenance: 10mg/kg/dose 4 x per day for 11 doses) and NAC (initial: 140mg/kg/dose; maintenance: 70mg/kg/dose 6 x per day for 17 doses) or the placebo via nasogastric (NG) or orogastric (OG) tube for 3 days.
Placebo contents include equal volumes and dosing regimens of lactose powder (for opacity) suspended in Ora-Plus and normal saline.
Otros nombres:
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¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Number of Participants Who Experienced Adverse Events
Periodo de tiempo: 14 days after drug administration
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The number of patients experiencing one or more of the following adverse events: Acute renal failure Anaphylaxis Acute respiratory distress syndrome Intracranial infection/abscess Arrhythmia, atrial Arrhythmia, ventricular Bradycardia Cardiac arrest Catheter positive culture Cerebrospinal fluid leak Decubitis Deep vein thrombosis Diabetes Insipidus Emesis Extraaxial hematoma Gastrointestinal bleed Gastritis Hematuria Hemorrhage, other Hemoperitonium Hemothorax Hepatitis Hydrocephalus Hypotension Hypoxemia Infection, other Intraparenchymal hemorrhage Intraventricular hemorrhage Meningitis/ventriculitis Multiorgan dysfunction syndrome Myocardial ischemia Pancreatitis Pericarditis Peritonitis Pneumothorax Pulmonary edema Pulmonary embolism Respiratory arrest Seizures Sepsis Syndrome of inappropriate antidiuretic hormone Transtentorial herniation Withdrawal of Life Support Other SAE causing re-hospitalization Other SAE |
14 days after drug administration
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Antioxidant Reserve
Periodo de tiempo: Within 5 days of injury
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Antioxidant reserves in CSF and serum will be calculated in both treatment arms and compared.
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Within 5 days of injury
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Colaboradores e Investigadores
Patrocinador
Colaboradores
Investigadores
- Investigador principal: Michael J Bell, MD, University of Pittsburgh
- Director de estudio: Robert SB Clark, MD, University of Pittsburgh
Publicaciones y enlaces útiles
Publicaciones Generales
- Hagos FT, Empey PE, Wang P, Ma X, Poloyac SM, Bayir H, Kochanek PM, Bell MJ, Clark RSB. Exploratory Application of Neuropharmacometabolomics in Severe Childhood Traumatic Brain Injury. Crit Care Med. 2018 Sep;46(9):1471-1479. doi: 10.1097/CCM.0000000000003203.
- Clark RSB, Empey PE, Bayir H, Rosario BL, Poloyac SM, Kochanek PM, Nolin TD, Au AK, Horvat CM, Wisniewski SR, Bell MJ. Phase I randomized clinical trial of N-acetylcysteine in combination with an adjuvant probenecid for treatment of severe traumatic brain injury in children. PLoS One. 2017 Jul 7;12(7):e0180280. doi: 10.1371/journal.pone.0180280. eCollection 2017.
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio
Finalización primaria (Actual)
Finalización del estudio (Actual)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Estimar)
Actualizaciones de registros de estudio
Última actualización publicada (Estimar)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Enfermedades Cerebrales
- Enfermedades del Sistema Nervioso Central
- Enfermedades del Sistema Nervioso
- Heridas y Lesiones
- Trauma craneoencefálico
- Trauma, Sistema Nervioso
- Lesiones Cerebrales
- Lesiones Cerebrales Traumáticas
- Efectos fisiológicos de las drogas
- Mecanismos moleculares de acción farmacológica
- Agentes antiinfecciosos
- Agentes Antivirales
- Agentes antirreumáticos
- Agentes Protectores
- Agentes del sistema respiratorio
- Antioxidantes
- Antídotos
- Eliminadores de radicales libres
- Supresores de gota
- Expectorantes
- Agentes renales
- Agentes uricosúricos
- Acetilcisteína
- N-monoacetilcistina
- Probenecid
Otros números de identificación del estudio
- NS069247
- 1R01NS069247-01 (Subvención/contrato del NIH de EE. UU.)
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Ensayos clínicos sobre Probenecid and N-acetyl cysteine
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Charles University, Czech RepublicAún no reclutandoAtrofia Muscular Espinal (SMA)Chequia