Overcoming Membrane Transporters to Improve CNS Drug Delivery - Improving Brain Antioxidants After Traumatic Brain Injury

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Overcoming Membrane Transporters to Improve CNS Drug Delivery

Conditions
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Pediatric Traumatic Brain Injury

Intervention / Treatment
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* Drug: Probenecid and N-acetyl cysteine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Drug<br>Probenecid and N-acetyl cysteine will be administered at standard doses for the first 4 days after TBI. | Drug: Probenecid and N-acetyl cysteine<br>* 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.<br>|
| Placebo Comparator: Placebo<br>Placebos will be prepared for the two experimental drugs and administered at identical time periods. | Drug: Placebo<br>* 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.<br>* Other names: Ora Plus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Adverse Events | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antioxidant Reserve | Antioxidant reserves in CSF and serum will be calculated in both treatment arms and compared. | Within 5 days of injury | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Children, Brain injury, Trauma