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

Condition(s) targeted: Chorioamnionitis; Brain Injury

Intervention: N-acetylcysteine (Drug); Saline (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: Medical University of South Carolina

Official(s) and/or principal investigator(s):
Dorothea D. Jenkins, MD, Principal Investigator, Affiliation: Medical University of South Carolina
Eugene Chang, MD, Principal Investigator, Affiliation: Medical University of South Carolina (Obstetric Principal Investigator)

Overall contact:
Deanna Fanning, RN, Phone: 843-792-7021, Email: fanningd@musc.edu

The purpose of this trial to find the best dose of N-acetylcysteine to decrease brain injury in babies exposed to intrauterine infection without causing significant side effects.

Official title: Safety of N-acetylcysteine in Maternal Chorioamnionitis

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment

Primary outcome: mean blood pressure, cerebral perfusion, PT, histaminergic reactions

Secondary outcome: Pharmacokinetics of placental transport and CSF penetration- efficacy outcomes: NAA/choline ratio in MRS at 36 weeks gestation, cytokine levels in plasma and CSF, as related to NAC concentrations

Detailed description: Chorioamnionitits is an intrauterine infection—an infection in the fluid and membranes surrounding the baby in utero. The infection, and the baby's response to the infection, can cause inflammation in the baby's brain which affects development. 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). Brain injury, particularly CP, has been shown to be 4-9 times higher in babies exposed to intrauterine infection than in normal infants. Treating both the mother and baby with antibiotics is part of routine care, however this has not been shown to change the risk for brain injury in the baby.

N-acetylcysteine (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. There are extensive clinical experience and safety data in pregnant mothers and preterm infants, established from acetaminophen overdose and European studies of NAC for prevention of chronic lung disease of prematurity.

In this pilot clinical trial, scientists will determine the safety of two different doses of NAC given to pregnant women who present with chorioamnionitis at greater than 24 weeks gestation.

In the trial, intravenous NAC will be given to mothers antenatally (and to their infants postnatally) who present with the diagnosis of chorioamnionitis, to evaluate safety and pharmacokinetics (PK) in mothers and infants. Mothers at 24 weeks gestation or greater and their infants will be randomized to receive either saline or one of two different doses of NAC within 4 hours of a clinical diagnosis of chorioamnionitis. NAC will be given to the mothers every 6 hours until delivery and every 12 hours to the infants after delivery for 2 days.

Information gained from this trial will be used to determine the best dose of NAC and to help estimate effect and sample sizes for a subsequent large clinical trial.

Minimum age: 13 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

Participants must have 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 must have none of the following:

- Asthma

- 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

Deanna Fanning, RN, Phone: 843-792-7021, Email: fanningd@musc.edu

Medical University of South Carolina, Charleston, South Carolina 29425, United States; Recruiting
Deanna Fanning, RN, Phone: 843-792-7021, Email: fanningd@musc.edu
Dorothea D. Jenkins, MD, Principal Investigator
Eugene Chang, MD, Principal Investigator
Denise Mulvihill, MD, Sub-Investigator
Don West, PharmD, Sub-Investigator
Sandra Garner, PharmD, Sub-Investigator
Toby Cox, PharmD, Sub-Investigator
Anthony Hlavachek, MD, Sub-Investigator
Renee Martin, PhD, Sub-Investigator
John Schwacke, PhD, Sub-Investigator

Related publications:

Grether JK, Nelson KB. Maternal infection and cerebral palsy in infants of normal birth weight. JAMA. 1997 Jul 16;278(3):207-11. Erratum in: JAMA 1998 Jan 14;279(2):118.

Wu YW, Colford JM Jr. Chorioamnionitis as a risk factor for cerebral palsy: A meta-analysis. JAMA. 2000 Sep 20;284(11):1417-24. Review.

Yoon BH, Romero R, Park JS, Kim CJ, Kim SH, Choi JH, Han TR. Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol. 2000 Mar;182(3):675-81.

Kramer BW, Moss TJ, Willet KE, Newnham JP, Sly PD, Kallapur SG, Ikegami M, Jobe AH. Dose and time response after intraamniotic endotoxin in preterm lambs. Am J Respir Crit Care Med. 2001 Sep 15;164(6):982-8.

Garnier Y, Coumans AB, Jensen A, Hasaart TH, Berger R. Infection-related perinatal brain injury: the pathogenic role of impaired fetal cardiovascular control. J Soc Gynecol Investig. 2003 Dec;10(8):450-9. Review.

Back SA, Gan X, Li Y, Rosenberg PA, Volpe JJ. Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion. J Neurosci. 1998 Aug 15;18(16):6241-53.

Paintlia MK, Paintlia AS, Barbosa E, Singh I, Singh AK. N-acetylcysteine prevents endotoxin-induced degeneration of oligodendrocyte progenitors and hypomyelination in developing rat brain. J Neurosci Res. 2004 Nov 1;78(3):347-61.

Khan M, Sekhon B, Jatana M, Giri S, Gilg AG, Sekhon C, Singh I, Singh AK. Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke. J Neurosci Res. 2004 May 15;76(4):519-27.

Beloosesky R, Gayle DA, Amidi F, Nunez SE, Babu J, Desai M, Ross MG. N-acetyl-cysteine suppresses amniotic fluid and placenta inflammatory cytokine responses to lipopolysaccharide in rats. Am J Obstet Gynecol. 2006 Jan;194(1):268-73.

Ahola T, Fellman V, Laaksonen R, Laitila J, Lapatto R, Neuvonen PJ, Raivio KO. Pharmacokinetics of intravenous N-acetylcysteine in pre-term new-born infants. Eur J Clin Pharmacol. 1999 Nov;55(9):645-50.

Starting date: August 2008
Last updated: September 10, 2009