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

Phase 1

Completed

• Conditions: Pediatric Traumatic Brain Injury
• Interventions: Drug: Probenecid and N-acetyl cysteine; Drug: Placebo

• Registration Number: NCT01322009
• Lead Sponsor: University of Pittsburgh

Brief Summary

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

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.

Study Timeline

• Study Start: 2011-03
• Study First Submitted: 2011-03-22
• Study First Submitted QC: 2011-03-23
• Study First Posted: 2011-03-24
• Primary Completion: 2013-12
• Study Completion: 2015-03
• Results First Submitted: 2016-05-19
• Status Verified: 2016-07
• Results First Submitted QC: 2016-07-01
• Last Update Submitted: 2016-07-01
• Results First Posted: 2016-08-15
• Last Update Posted: 2016-08-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 14

Inclusion Criteria

• Children (age 2 - 18 y) with severe TBI (GCS < or = 8) with an externalized ventricular drain placed for measurement of intracranial pressure

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Exclusion Criteria

1. Brain dead on admission to ICU

2. Pregnancy

3. Contraindications to enteral medications

4. Contraindications to probenecid:

   • status epilepticus
   • blood dyscrasias
   • under 2 years-of-age
   • coadministration of salicylates
   • renal dysfunction or urate kidney stones
   • hypersensitivity to probenecid

5. Contraindications to N-acetylcysteine: hypersensitivity to N-acetylcysteine

6. Family unwilling to consent

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Drug	Probenecid and N-acetyl cysteine	Probenecid and N-acetyl cysteine will be administered at standard doses for the first 4 days after TBI.
Placebo	Placebo	Placebos will be prepared for the two experimental drugs and administered at identical time periods.

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Experienced Adverse Events	14 days after drug administration	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

Secondary Outcome Measures

Name	Time	Method
Antioxidant Reserve	Within 5 days of injury	Antioxidant reserves in CSF and serum will be calculated in both treatment arms and compared.

Trial Locations

Locations (1)

Children's Hospital of Pittsburgh of UPMC; 🇺🇸 Pittsburgh, Pennsylvania, United States