Clinical trial NCT00724594: Safety of N-acetylcysteine in Maternal Chorioamnionitis (NAC in Chorio)
Official title: Safety of N-acetylcysteine in Maternal Chorioamnionitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Chorioamnionitis
Brain Injury
Keywords: chorioamnionitis
maternal chorioamnionitis
neonatal white matter injury
N-acetylcysteine
NAC
anti-oxidant treatment
Lead sponsor: Medical University of South Carolina
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2008-07-29
Enrollment: 46
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this trial was to find the best dose of N-acetylcysteine (NAC) to decrease brain injury in babies exposed to intrauterine infection without causing significant side effects.

Detailed description: Chorioamnionitits is an infection in the fluid and membranes surrounding the baby in utero. Intrauterine infection is associated with significant white and grey matter brain injury in newborns and is particularly important in the pathogenesis of periventricular leukomalacia (PVL) and cerebral palsy (CP). CP has been shown to be 4-9 times higher in babies exposed to intrauterine infection than in normal infants. Antibiotics have not changed the risk for brain injury in the newborn.

NAC is a promising anti-oxidant therapy that has shown effective neuroprotection in an animal model of chorioamnionitis, and has a favorable safety profile with limited and manageable side effects.

In this trial, intravenous NAC was given to mothers antenatally and to their infants postnatally, who presented with the diagnosis of chorioamnionitis, to evaluate safety and pharmacokinetics (PK) in mothers and infants. Mothers at ≥24 weeks gestation and their infants were randomized to receive either saline NAC within 4 hours of a clinical diagnosis of chorioamnionitis. Infants were stratified into term (≥ 33wk) and preterm (24-32wk) cohorts, due to different expected rates of metabolism and clearance.

Information gained from this trial will be used to determine how rapidly NAC is metabolized by mother, fetus, infant, and the ability of NAC to cross placenta. This study will also elucidate the safety of NAC in the setting of chorioamnionitis for fetal neuroprotection.

Eligibility criteria: Inclusion Criteria:

Participants had all of the following to qualify:

* Chorioamnionitis, defined as either 1) clinical diagnosis of choriomanionitis 2) maternal fever greater than or equal to 100 degrees F in the presence of rupture of membranes or 2 of the following: uterine tenderness, maternal WBC \> 15,000 cells/mm, fetal tachycardia \> 160 bpm, malodorous amniotic fluid, or in preterm group only, rupture of membranes and active preterm labor.
* Gestational age ≥ 24 completed weeks, by first trimester ultrasound or date of last menstrual period.
* No greater than 4 hours from onset of fever or diagnosis.

Exclusion Criteria:

Participants had none of the following:

* Asthma, steroid-dependent
* Clinical sepsis, whether viral or bacterial in nature, defined as fever with signs of cardiovascular compromise in mother (blood pressure \< 90/50, heart rate \> 120 bpm, need for oxygen due to maternal saturations below 92%, pneumonia, pyelonephritis, or meningitis)
* Seizure disorder
* Fetal weight or biparietal diameter less than the 10th% for gestational age
* Suspected major genetic or congenital abnormality
* Fetal distress which demands immediate delivery (poor fetal biophysical profile, late decelerations, sinusoidal fetal heart rate pattern)
* Participation in another therapeutic clinical trial

Primary outcomes:
measure: NAC Terminal Elimination Half-life
timeFrame: prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion
measure: NAC Volume of Distribution
timeFrame: prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion
measure: NAC Total Body Clearance
timeFrame: prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion
measure: NAC Concentrations
timeFrame: Peak: 30 minutes after NAC infusion. Cord: at delivery
measure: Placental Transfer Ratio
timeFrame: At time of delivery
measure: Maternal and Infant Mean Blood Pressure Change
timeFrame: Maternal mean BP changes were pre/post dosing prior to delivery. Infant measurements were pre/post their first dosing
measure: Cerebral Blood Flow
timeFrame: after NAC infusion
measure: Prothrombin Time
timeFrame: after N-acetylcystiene or saline infusion
Secondary outcomes:
measure: Magnetic Resonance Spectroscopy of Infants
timeFrame: 36 - 40 weeks gestational age
measure: Cytokine Level IL-1Ra in Plasma
timeFrame: after N-acetylcysteine infusion
Other outcomes:
Locations:
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
Study officials:
affiliation: Medical University of South Carolina
name: Dorothea D. Jenkins, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical University of South Carolina (Obstetric Principal Investigator)
name: Eugene Chang, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wiest DB, Chang E, Fanning D, Garner S, Cox T, Jenkins DD. Antenatal pharmacokinetics and placental transfer of N-acetylcysteine in chorioamnionitis for fetal neuroprotection. J Pediatr. 2014 Oct;165(4):672-7.e2. doi: 10.1016/j.jpeds.2014.06.044. Epub 2014 Jul 23.
citation: Jenkins DD, Wiest DB, Mulvihill DM, Hlavacek AM, Majstoravich SJ, Brown TR, Taylor JJ, Buckley JR, Turner RP, Rollins LG, Bentzley JP, Hope KE, Barbour AB, Lowe DW, Martin RH, Chang EY. Fetal and Neonatal Effects of N-Acetylcysteine When Used for Neuroprotection in Maternal Chorioamnionitis. J Pediatr. 2016 Jan;168:67-76.e6. doi: 10.1016/j.jpeds.2015.09.076. Epub 2015 Nov 3.