Phase I randomized clinical trial of N-acetylcysteine in combination with an adjuvant probenecid for treatment of severe traumatic brain injury in children

<div><p>Background</p><p>There are no therapies shown to improve outcome after severe traumatic brain injury (TBI) in humans, a leading cause of morbidity and mortality. We sought to verify brain exposure of the systemically administered antioxidant N-acetylcysteine (NAC) and the synergistic adjuvant probenecid, and identify adverse effects of this drug combination after severe TBI in children.</p><p>Methods</p><p>IRB-approved, randomized, double-blind, placebo controlled Phase I study in children 2 to 18 years-of-age admitted to a Pediatric Intensive Care Unit after severe TBI (Glasgow Coma Scale [GCS] score ≤8) requiring an externalized ventricular drain for measurement of intracranial pressure (ICP). Patients were recruited from November 2011-August 2013. Fourteen patients (n = 7/group) were randomly assigned after obtaining informed consent to receive probenecid (25 mg/kg load, then 10 mg/kg/dose q6h×11 doses) and NAC (140 mg/kg load, then 70 mg/kg/dose q4h×17 doses), or placebos via naso/orogastric tube. Serum and CSF samples were drawn pre-bolus and 1–96 h after randomization and drug concentrations were measured via UPLC-MS/MS. Glasgow Outcome Scale (GOS) score was assessed at 3 months.</p><p>Results</p><p>There were no adverse events attributable to drug treatment. One patient in the placebo group was withdrawn due to adverse effects. In the treatment group, NAC concentrations ranged from 16,977.3±2,212.3 to 16,786.1±3,285.3 in serum and from 269.3±113.0 to 467.9±262.7 ng/mL in CSF, at 24 to 72 h post-bolus, respectively; and probenecid concentrations ranged from 75.4.3±10.0 to 52.9±25.8 in serum and 5.4±1.0 to 4.6±2.1 μg/mL in CSF, at 24 to 72 h post-bolus, respectively (mean±SEM). Temperature, mean arterial pressure, ICP, use of ICP-directed therapies, surveillance serum brain injury biomarkers, and GOS at 3 months were not different between groups.</p><p>Conclusions</p><p>Treatment resulted in detectable concentrations of NAC and probenecid in CSF and was not associated with undesirable effects after TBI in children.</p><p>Trial registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01322009" target="_blank">NCT01322009</a></p></div

Patient outcomes.

<p>Patient outcomes.</p

Serum and cerebrospinal fluid (CSF) N-acetylcysteine (NAC) and probenecid concentrations during study period.

<p>NAC (<i>A</i>) and probenecid (<i>B</i>) concentrations measured using ultra-high performance liquid chromatography-mass spectrometry (MS)/MS are shown for the placebo (red circles) and probenecid + NAC (Pro-NAC; open blue squares) groups. Data are mean and SEM; sample sizes noted in parentheses (n); LOQ = lower limit of quantification for the assay. Hashed lines represent drug administration times. ¹Sample attrition due to patient death, premature withdrawal from study due to adverse event (rash), inability to continue enteric administration of study drugs after removal of nasogastric tube, and/or removal of or inability to obtain CSF from externalized ventricular drain.</p

Serum brain injury biomarkers neuron specific enolase (NSE) and glial fibrillary acidic protein (GFAP) during study period.

<p>Individual NSE corrected for the degree of hemolysis (<i>A</i>) and GFAP (<i>B</i>) values for patients in the placebo (red circles) and probenecid + NAC (Pro-NAC; open blue squares) groups during the study period. There were no differences between groups for NSE (<i>P</i> = 0.441) or GFAP (<i>P</i> = 0.596). Time 0 is in reference to drug administration. Both groups started with seven patients/group. Sample attrition due to patient death, discontinuation of continuous monitoring, or insufficient quantity of serum available to perform the assay.</p

Medical interventions.

<p>Medical interventions.</p

Mean arterial pressure (MAP), intracranial pressure (ICP), and cerebral perfusion pressure (CPP) during study period.

<p>MAP (<i>A</i>), ICP (<i>B</i>), and CPP (<i>C</i>) in the placebo (red circles) and probenecid + NAC (Pro-NAC; open blue squares) groups during the study period. Time 0 refers to pediatric intensive care unit admission. Median time [range] to first drug dose for the placebo group was 20.5 [14.6–26.0] h and for the Pro-NAC group was 16.5 [8.8–22.0] h. Data are mean and SD; Both groups started with seven patients/group. Sample attrition due to patient death or discontinuation of continuous monitoring.</p

Baseline characteristics in the intention to-treat-population.

<p>Baseline characteristics in the intention to-treat-population.</p

Surgical interventions.

<p>Surgical interventions.</p

Adverse events and complications.

<p>Adverse events and complications.</p

CONSORT flow diagram.

<p>*in one patient support was withdrawn due to poor neurological prognosis; one patient developed a diffuse rash after administration of study drugs and further administration was discontinued; in one patient the nasogastric tube was removed after extubation and discontinuation of mechanical ventilation, and was not replaced as per study protocol preventing further administration of study drugs.</p