Safety of N-acetylcysteine in Maternal Chorioamnionitis (NAC in Chorio)

Brain Injury Clinical Trial

Official title:

Safety of N-acetylcysteine in Maternal Chorioamnionitis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00724594
• Other study ID #: R01NS052448
• Secondary ID: R01NS052448
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: August 2008
• Est. completion date: August 2014

Study information

• Verified date: March 2021
• Source: Medical University of South Carolina
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 46
• Est. completion date: August 2014
• Est. primary completion date: July 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 13 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Brain Injuries
• Brain Injury
• Chorioamnionitis

Intervention

Drug:
• N-acetylcysteine
NAC (100 mg/kg/dose) was given intravenously to mothers within 4 hours of diagnosis of chorioamnionitis, and every 6 hours until delivery. NAC was given to preterm (12.5 mg/kg/dose) and term infants (25 mg/kg/dose) every 12 hours for 5 doses after birth.
• Control
Saline was given in the same volume, at the same timing as NAC infusions

Locations

Country	Name	City	State
United States	Medical University of South Carolina	Charleston	South Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Medical University of South Carolina	National Institute of Neurological Disorders and Stroke (NINDS)

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 201 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	NAC Terminal Elimination Half-life		prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion
Primary	NAC Volume of Distribution		prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion
Primary	NAC Total Body Clearance		prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion
Primary	NAC Concentrations		Peak: 30 minutes after NAC infusion. Cord: at delivery
Primary	Placental Transfer Ratio	Ratio of NAC concentration in cord to maternal venous blood	At time of delivery
Primary	Maternal and Infant Mean Blood Pressure Change		Maternal mean BP changes were pre/post dosing prior to delivery. Infant measurements were pre/post their first dosing
Primary	Cerebral Blood Flow	Resistive index in middle cerebral artery (MCA)	after NAC infusion
Primary	Prothrombin Time	prothrombin clotting time	after N-acetylcystiene or saline infusion
Secondary	Magnetic Resonance Spectroscopy of Infants	ratio of myoInositol / NAA concentrations in basal ganglia	36 - 40 weeks gestational age
Secondary	Cytokine Level IL-1Ra in Plasma	anti-inflammatory cytokine Interleukin -1 Receptor alpha (IL-1Ra)	after N-acetylcysteine infusion