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

This study has been completed.
Sponsor:
Collaborator:
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Dorothea D. Jenkins, Medical University of South Carolina
ClinicalTrials.gov Identifier:
NCT00724594
First received: July 28, 2008
Last updated: May 8, 2015
Last verified: May 2015
  Purpose
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.

Condition Intervention Phase
Chorioamnionitis
Brain Injury
Drug: N-acetylcysteine
Drug: Control
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
Official Title: Safety of N-acetylcysteine in Maternal Chorioamnionitis

Resource links provided by NLM:


Further study details as provided by Medical University of South Carolina:

Primary Outcome Measures:
  • NAC Terminal Elimination Half-life [ Time Frame: prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion ] [ Designated as safety issue: No ]
  • NAC Volume of Distribution [ Time Frame: prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion ] [ Designated as safety issue: No ]
  • NAC Total Body Clearance [ Time Frame: prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion ] [ Designated as safety issue: No ]
  • NAC Concentrations [ Time Frame: Peak: 30 minutes after NAC infusion. Cord: at delivery ] [ Designated as safety issue: No ]
  • Placental Transfer Ratio [ Time Frame: At time of delivery ] [ Designated as safety issue: No ]
    Ratio of NAC concentration in cord to maternal venous blood

  • Maternal and Infant Mean Blood Pressure Change [ Time Frame: Maternal mean BP changes were pre/post dosing prior to delivery. Infant measurements were pre/post their first dosing ] [ Designated as safety issue: Yes ]
  • Cerebral Blood Flow [ Time Frame: prior to delivery and in newborn after delivery, during 2 days of NAC infusion ] [ Designated as safety issue: Yes ]
  • PT [ Time Frame: prior to delivery and in newborn DOL1 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Magnetic Resonance Spectroscopy of Infants [ Time Frame: 36 - 40 weeks gestational age ] [ Designated as safety issue: No ]
  • Cytokine Levels in Plasma and CSF [ Time Frame: During 2 days of NAC infusion ] [ Designated as safety issue: No ]

Enrollment: 46
Study Start Date: August 2008
Study Completion Date: August 2014
Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: N-acetylcysteine
Mother/infant pairs were stratified by gestational age into premature (P) and term (T) cohorts.
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.
Other Name: Acetadote, NAC
Active Comparator: Control
Mother/infant pairs were stratified by gestational age into premature (P) and term (T) cohorts.
Drug: Control
Saline was given in the same volume, at the same timing as NAC infusions
Other Name: Saline

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

Ages Eligible for Study:   13 Years and older   (Child, Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00724594

Locations
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
Sponsors and Collaborators
Medical University of South Carolina
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
Principal Investigator: Dorothea D. Jenkins, MD Medical University of South Carolina
Principal Investigator: Eugene Chang, MD Medical University of South Carolina (Obstetric Principal Investigator)
  More Information

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Dorothea D. Jenkins, Associate Professor, Medical University of South Carolina
ClinicalTrials.gov Identifier: NCT00724594     History of Changes
Other Study ID Numbers: R01NS052448 
Study First Received: July 28, 2008
Results First Received: January 9, 2015
Last Updated: May 8, 2015
Health Authority: United States: Federal Government

Keywords provided by Medical University of South Carolina:
chorioamnionitis
maternal chorioamnionitis
neonatal white matter injury
N-acetylcysteine
NAC
anti-oxidant treatment

Additional relevant MeSH terms:
Brain Injuries
Chorioamnionitis
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Wounds and Injuries
Fetal Diseases
Pregnancy Complications
Fetal Membranes, Premature Rupture
Obstetric Labor Complications
Placenta Diseases
Acetylcysteine
N-monoacetylcystine
Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes

ClinicalTrials.gov processed this record on September 30, 2016