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.

Study Overview

• Status: Completed
• Conditions: Pediatric Traumatic Brain Injury
• Intervention / Treatment: Drug: Probenecid and N-acetyl cysteine; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh of UPMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Pittsburgh
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); National Institutes of Health (NIH)
• Investigators: Principal Investigator: Michael J Bell, MD, University of Pittsburgh; Study Director: Robert SB Clark, MD, University of Pittsburgh

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): March 1, 2015

Study Registration Dates

• First Submitted: March 22, 2011
• First Submitted That Met QC Criteria: March 23, 2011
• First Posted (Estimate): March 24, 2011

Study Record Updates

• Last Update Posted (Estimate): August 15, 2016
• Last Update Submitted That Met QC Criteria: July 1, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: Children; Trauma; Brain injury
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Brain Injuries, Traumatic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antirheumatic Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Gout Suppressants; Expectorants; Renal Agents; Uricosuric Agents; Acetylcysteine; N-monoacetylcystine; Probenecid
• Other Study ID Numbers: NS069247; 1R01NS069247-01 (U.S. NIH Grant/Contract)