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

NCT ID: NCT01322009

Last Updated: 2016-08-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 14 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-03-31
• Study Completion Date: 2015-03-31

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.

Conditions

Pediatric Traumatic Brain Injury

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Drug

Probenecid and N-acetyl cysteine will be administered at standard doses for the first 4 days after TBI.

Group Type: EXPERIMENTAL

Probenecid and N-acetyl cysteine

Intervention Type: DRUG

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

Placebos will be prepared for the two experimental drugs and administered at identical time periods.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Ora Plus

Eligibility 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

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

National Institute of Neurological Disorders and Stroke (NINDS)

NIH

Sponsor Role: collaborator

University of Pittsburgh

OTHER

Sponsor Role: lead

Responsible Party

Robert Clark, MD

Critical Care Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Michael J Bell, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pittsburgh

Robert SB Clark, MD

Role: STUDY_DIRECTOR

University of Pittsburgh

Locations

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States

Countries

United States

References

Clark RSB, Empey PE, Kochanek PM, Bell MJ. N-Acetylcysteine and Probenecid Adjuvant Therapy for Traumatic Brain Injury. Neurotherapeutics. 2023 Oct;20(6):1529-1537. doi: 10.1007/s13311-023-01422-z. Epub 2023 Aug 18.

Reference Type: DERIVED

PMID: 37596428 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29742587 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28686657 (View on PubMed)

Other Identifiers

1R01NS069247-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NS069247

Identifier Type: -

Identifier Source: org_study_id