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

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ClinicalTrials.gov Identifier: NCT01322009
Recruitment Status : Completed
First Posted : March 24, 2011
Results First Posted : August 15, 2016
Last Update Posted : August 15, 2016
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

Tracking Information
First Submitted Date  ICMJE March 22, 2011
First Posted Date  ICMJE March 24, 2011
Results First Submitted Date  ICMJE May 19, 2016
Results First Posted Date  ICMJE August 15, 2016
Last Update Posted Date August 15, 2016
Study Start Date  ICMJE March 2011
Actual Primary Completion Date December 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 1, 2016)
Number of Participants Who Experienced Adverse Events [ Time Frame: 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
Original Primary Outcome Measures  ICMJE
 (submitted: March 23, 2011)
Adverse Events [ Time Frame: 14 days after drug administration ]
A number of a prior defined adverse events have been defined. The number of adverse events in the treatment arms will be calculated and compared.
Change History Complete list of historical versions of study NCT01322009 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 23, 2011)
Antioxidant Reserve [ Time Frame: Within 5 days of injury ]
Antioxidant reserves in CSF and serum will be calculated in both treatment arms and compared.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Overcoming Membrane Transporters to Improve CNS Drug Delivery - Improving Brain Antioxidants After Traumatic Brain Injury
Official Title  ICMJE Overcoming Membrane Transporters to Improve CNS Drug Delivery
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Pediatric Traumatic Brain Injury
Intervention  ICMJE
  • 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.
  • 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
Study Arms  ICMJE
  • Experimental: Drug
    Probenecid and N-acetyl cysteine will be administered at standard doses for the first 4 days after TBI.
    Intervention: Drug: Probenecid and N-acetyl cysteine
  • Placebo Comparator: Placebo
    Placebos will be prepared for the two experimental drugs and administered at identical time periods.
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 1, 2016)
14
Original Estimated Enrollment  ICMJE
 (submitted: March 23, 2011)
20
Actual Study Completion Date  ICMJE March 2015
Actual Primary Completion Date December 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 18 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01322009
Other Study ID Numbers  ICMJE NS069247
1R01NS069247-01 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Robert Clark, MD, University of Pittsburgh
Study Sponsor  ICMJE University of Pittsburgh
Collaborators  ICMJE
  • National Institutes of Health (NIH)
  • National Institute of Neurological Disorders and Stroke (NINDS)
Investigators  ICMJE
Principal Investigator: Michael J Bell, MD University of Pittsburgh
Study Director: Robert SB Clark, MD University of Pittsburgh
PRS Account University of Pittsburgh
Verification Date July 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP