Pediatric Traumatic Brain Injury
Conditions
Keywords
Children, Brain injury, Trauma
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.
Interventions
DRUGProbenecid 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.
DRUGPlacebo
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.
Sponsors
National Institutes of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
University of Pittsburgh
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to 18 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Antioxidant Reserve | Within 5 days of injury | Antioxidant reserves in CSF and serum will be calculated in both treatment arms and compared. |
Countries
United States
Participant flow
Recruitment details
Children 2-18 years-of-age after severe TBI (Glasgow Coma Scale \[GCS\] score ≤8) recruited from November 2011-September 2013 at a single, tertiary Children's Hospital.
Participants by arm
| Arm | Count |
|---|---|
| Drug Probenecid and N-acetyl cysteine will be administered at standard doses for the first 4 days after TBI.
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. | 7 |
| Placebo Placebos will be prepared for the two experimental drugs and administered at identical time periods.
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. | 7 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 0 | 1 |
| Overall Study | ng tube discontinued | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Drug | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 7 Participants | 7 Participants | 14 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 9.7 years STANDARD_DEVIATION 5.7 | 8.6 years STANDARD_DEVIATION 4.9 | 9.1 years STANDARD_DEVIATION 5.1 |
| Region of Enrollment United States | 7 participants | 7 participants | 14 participants |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 4 Participants | 6 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 7 | 1 / 7 |
| serious Total, serious adverse events | 0 / 7 | 1 / 7 |
Outcome results
Primary
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
Time frame: 14 days after drug administration
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drug | Number of Participants Who Experienced Adverse Events | 0 participants |
| Placebo | Number of Participants Who Experienced Adverse Events | 2 participants |
Secondary
Antioxidant Reserve
Antioxidant reserves in CSF and serum will be calculated in both treatment arms and compared.
Time frame: Within 5 days of injury
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Drug | Antioxidant Reserve | 751 reactive oxygen species scavenged | Standard Error 85 |
| Placebo | Antioxidant Reserve | 735 reactive oxygen species scavenged | Standard Error 117 |
p-value: >0.05ANOVA