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Overcoming Membrane Transporters to Improve CNS Drug Delivery - Improving Brain Antioxidants After Traumatic Brain Injury (Pro-NAC)

This study has been completed.
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Robert Clark, MD, University of Pittsburgh
ClinicalTrials.gov Identifier:
NCT01322009
First received: March 22, 2011
Last updated: July 1, 2016
Last verified: July 2016
  Purpose

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.


Condition Intervention Phase
Pediatric Traumatic Brain Injury
Drug: Probenecid and N-acetyl cysteine
Drug: Placebo
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Overcoming Membrane Transporters to Improve CNS Drug Delivery

Resource links provided by NLM:


Further study details as provided by University of Pittsburgh:

Primary Outcome Measures:
  • Number of Participants Who Experienced Adverse Events [ Time Frame: 14 days after drug administration ] [ Designated as safety issue: Yes ]

    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:
  • Antioxidant Reserve [ Time Frame: Within 5 days of injury ] [ Designated as safety issue: No ]
    Antioxidant reserves in CSF and serum will be calculated in both treatment arms and compared.


Enrollment: 14
Study Start Date: March 2011
Study Completion Date: March 2015
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Ora Plus

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.

  Eligibility

Ages Eligible for Study:   2 Years to 18 Years   (Child, Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01322009

Locations
United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States, 15213
Sponsors and Collaborators
University of Pittsburgh
National Institutes of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
Principal Investigator: Michael J Bell, MD University of Pittsburgh
Study Director: Robert SB Clark, MD University of Pittsburgh
  More Information

Responsible Party: Robert Clark, MD, Critical Care Medicine, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT01322009     History of Changes
Other Study ID Numbers: NS069247  1R01NS069247-01 
Study First Received: March 22, 2011
Results First Received: May 19, 2016
Last Updated: July 1, 2016
Health Authority: United States: Institutional Review Board

Keywords provided by University of Pittsburgh:
Children
Brain injury
Trauma

Additional relevant MeSH terms:
Wounds and Injuries
Brain Injuries
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Acetylcysteine
N-monoacetylcystine
Probenecid
Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes
Uricosuric Agents
Gout Suppressants
Antirheumatic Agents
Renal Agents

ClinicalTrials.gov processed this record on September 23, 2016