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

Sponsor
Medical University of South Carolina (Other)
Overall Status
Completed
CT.gov ID
NCT00724594
Collaborator
National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
46
1
2
72
0.6

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
46 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Single (Participant)
Primary Purpose:
Treatment
Official Title:
Safety of N-acetylcysteine in Maternal Chorioamnionitis
Study Start Date :
Aug 1, 2008
Actual Primary Completion Date :
Jul 1, 2014
Actual Study Completion Date :
Aug 1, 2014

Arms and Interventions

Arm Intervention/Treatment
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 Names:
  • 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 Names:
  • Saline
  • Outcome Measures

    Primary Outcome Measures

    1. NAC Terminal Elimination Half-life [prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion]

    2. NAC Volume of Distribution [prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion]

    3. NAC Total Body Clearance [prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion]

    4. NAC Concentrations [Peak: 30 minutes after NAC infusion. Cord: at delivery]

    5. Placental Transfer Ratio [At time of delivery]

      Ratio of NAC concentration in cord to maternal venous blood

    6. 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]

    7. Cerebral Blood Flow [after NAC infusion]

      Resistive index in middle cerebral artery (MCA)

    8. Prothrombin Time [after N-acetylcystiene or saline infusion]

      prothrombin clotting time

    Secondary Outcome Measures

    1. Magnetic Resonance Spectroscopy of Infants [36 - 40 weeks gestational age]

      ratio of myoInositol / NAA concentrations in basal ganglia

    2. Cytokine Level IL-1Ra in Plasma [after N-acetylcysteine infusion]

      anti-inflammatory cytokine Interleukin -1 Receptor alpha (IL-1Ra)

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    13 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Locations

    Site City State Country Postal Code
    1 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)

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Dorothea D. Jenkins, Associate Professor, Medical University of South Carolina
    ClinicalTrials.gov Identifier:
    NCT00724594
    Other Study ID Numbers:
    • R01NS052448
    • R01NS052448
    First Posted:
    Jul 29, 2008
    Last Update Posted:
    Apr 12, 2021
    Last Verified:
    Mar 1, 2021
    Keywords provided by Dorothea D. Jenkins, Associate Professor, Medical University of South Carolina
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail Due two enrolling two sets of twins (one set in the preterm/NAC group, and one set in the preterm/control group), our study included 24 infants and 22 mothers.
    Arm/Group Title NAC Infant Control Infant NAC Maternal Control Maternal
    Arm/Group Description Infants treated with N-acetylcysteine Infants treated with saline Mothers of infants treated with N-acetylcysteine Mothers of infants treated with saline
    Period Title: Overall Study
    STARTED 12 12 11 11
    COMPLETED 12 12 11 10
    NOT COMPLETED 0 0 0 1

    Baseline Characteristics

    Arm/Group Title NAC Infant Control Infant NAC Maternal Control Maternal Total
    Arm/Group Description Infants treated with N-acetylcysteine Infants treated with saline Mothers of infants treated with N-acetylcysteine Mothers of infants treated with saline Total of all reporting groups
    Overall Participants 12 12 11 11 46
    Age, Customized (participants) [Number]
    Preterm Infants
    7
    58.3%
    7
    58.3%
    NA
    NaN
    NA
    NaN
    NA
    NaN
    Term Infants
    5
    41.7%
    5
    41.7%
    NA
    NaN
    NA
    NaN
    NA
    NaN
    Mothers aged 18-45years
    NA
    NaN
    NA
    NaN
    11
    100%
    11
    100%
    NA
    NaN
    Sex: Female, Male (Count of Participants)
    Female
    5
    41.7%
    6
    50%
    11
    100%
    11
    100%
    33
    71.7%
    Male
    7
    58.3%
    6
    50%
    0
    0%
    0
    0%
    13
    28.3%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    9
    75%
    5
    41.7%
    8
    72.7%
    4
    36.4%
    26
    56.5%
    White
    3
    25%
    7
    58.3%
    3
    27.3%
    7
    63.6%
    20
    43.5%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    12
    100%
    12
    100%
    11
    100%
    11
    100%
    46
    100%

    Outcome Measures

    1. Primary Outcome
    Title NAC Terminal Elimination Half-life
    Description
    Time Frame prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title NAC Maternal NAC Preterm Infants NAC Term Infants
    Arm/Group Description Mothers treated with N-acetylcysteine prior to delivery of infant Preterm infants treated with N-acetylcysteine Term infants treated with N-acetylcysteine
    Measure Participants 11 7 5
    Mean (Standard Deviation) [hours]
    1.2
    (0.2)
    7.5
    (2.0)
    5.1
    (1.3)
    2. Primary Outcome
    Title NAC Volume of Distribution
    Description
    Time Frame prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title NAC Maternal NAC Preterm Infants NAC Term Infants
    Arm/Group Description Mothers treated with N-acetylcysteine prior to delivery of infant Preterm infants treated with N-acetylcysteine Term infants treated with N-acetylcysteine
    Measure Participants 11 7 5
    Mean (Standard Deviation) [L/kg]
    0.41
    (0.07)
    0.47
    (0.04)
    0.38
    (0.09)
    3. Primary Outcome
    Title NAC Total Body Clearance
    Description
    Time Frame prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title NAC Maternal NAC Preterm Infants NAC Term Infants
    Arm/Group Description Mothers treated with N-acetylcysteine prior to delivery of infant Preterm infants treated with N-acetylcysteine Term infants treated with N-acetylcysteine
    Measure Participants 11 7 5
    Mean (Standard Deviation) [mL/h/kg]
    255
    (61)
    45.0
    (8.2)
    53.7
    (11.3)
    4. Primary Outcome
    Title NAC Concentrations
    Description
    Time Frame Peak: 30 minutes after NAC infusion. Cord: at delivery

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title NAC Maternal NAC Preterm Infants NAC Term Infants
    Arm/Group Description Mothers treated with N-acetylcysteine prior to delivery Preterm infants treated with N-acetylcysteine Term infants treated with N-acetylcysteine
    Measure Participants 11 7 5
    Peak NAC concentration in plasma
    1222
    (415)
    49.0
    (14.9)
    92.3
    (69.2)
    NAC cord concentration
    NA
    (NA)
    370.7
    (199.2)
    639.7
    (409.4)
    5. Primary Outcome
    Title Placental Transfer Ratio
    Description Ratio of NAC concentration in cord to maternal venous blood
    Time Frame At time of delivery

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title NAC Maternal
    Arm/Group Description Mothers treated with N-acetylcysteine prior to birth
    Measure Participants 12
    Mean (Standard Deviation) [ratio]
    1.4
    (0.8)
    6. Primary Outcome
    Title Maternal and Infant Mean Blood Pressure Change
    Description
    Time Frame Maternal mean BP changes were pre/post dosing prior to delivery. Infant measurements were pre/post their first dosing

    Outcome Measure Data

    Analysis Population Description
    The infant and maternal populations analyzed for this portion are incomplete, as not all individuals had paired before/after blood pressure measurements at this time point.
    Arm/Group Title NAC Infants Control Infants NAC Maternal Control Maternal
    Arm/Group Description Infants treated with N-acetylcysteine Infants treated with saline Mothers treated with N-acetylcysteine prior to delivery Mothers treated with saline prior to delivery
    Measure Participants 10 7 11 10
    Mean (Standard Deviation) [mmHg]
    -1.2
    (13)
    2.1
    (11)
    1
    (12)
    2
    (10)
    7. Primary Outcome
    Title Cerebral Blood Flow
    Description Resistive index in middle cerebral artery (MCA)
    Time Frame after NAC infusion

    Outcome Measure Data

    Analysis Population Description
    blood flow resistive indices after first dose of N-acetylcysteine or saline
    Arm/Group Title NAC Term Infants Control Term Infants NAC Preterm Infants Control Preterm Infants
    Arm/Group Description Term Infants treated with N-acetylcysteine Term Infants treated with saline Preterm Infants treated with N-acetylcysteine Preterm Infants treated with saline
    Measure Participants 5 4 6 5
    Mean (95% Confidence Interval) [units on a scale]
    0.93
    0.89
    0.92
    0.89
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection NAC Maternal, NAC Preterm Infants
    Comments Term infant cohort : NAC vs control H0= there will be no difference in resistive index in Middle Cerebral Artery after N-acetylcysteine or saline in the term cohort.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.9
    Comments not significant
    Method t-test, 2 sided
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection NAC Term Infants, Control Maternal
    Comments Preterm infant cohort: NAC vs control H0= there will be no difference in resisitive index in MCA after N-acetylcysteine or saline in preterm cohort
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.9
    Comments
    Method t-test, 2 sided
    Comments
    8. Primary Outcome
    Title Prothrombin Time
    Description prothrombin clotting time
    Time Frame after N-acetylcystiene or saline infusion

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title NAC Infant Control Infant NAC Maternal Control Maternal
    Arm/Group Description Infants treated with N-acetylcysteine Infants treated with saline Mothers of infants treated with N-acetylcysteine Mothers of infants treated with saline
    Measure Participants 8 6 11 11
    Mean (Standard Deviation) [seconds]
    19.5
    (2.5)
    19.0
    (4.0)
    14.2
    (0.6)
    14.4
    (1.2)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection NAC Term Infants, Control Maternal
    Comments Maternal cohort: NAC versus control l H0= PT will not be different in mothers after NAC or saline
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.9
    Comments not significant
    Method t-test, 2 sided
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection NAC Maternal, NAC Preterm Infants
    Comments Infant cohort: NAC versus control H0= prothrombin time will not be different in the infants after NAC or saline
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.9
    Comments
    Method t-test, 2 sided
    Comments
    9. Secondary Outcome
    Title Magnetic Resonance Spectroscopy of Infants
    Description ratio of myoInositol / NAA concentrations in basal ganglia
    Time Frame 36 - 40 weeks gestational age

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title NAC Infants Control Infants
    Arm/Group Description
    Measure Participants 7 9
    Mean (Standard Deviation) [ratio]
    1.09
    (0.31)
    1.34
    (0.20)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection NAC Maternal, NAC Preterm Infants
    Comments correcting for gestational age at birth
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.072
    Comments
    Method t-test, 2 sided
    Comments
    10. Secondary Outcome
    Title Cytokine Level IL-1Ra in Plasma
    Description anti-inflammatory cytokine Interleukin -1 Receptor alpha (IL-1Ra)
    Time Frame after N-acetylcysteine infusion

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title NAC Infants Control Infants
    Arm/Group Description
    Measure Participants 12 9
    Median (Inter-Quartile Range) [pg/ml]
    745
    8.3
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection NAC Maternal, NAC Preterm Infants
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.014
    Comments
    Method t-test, 2 sided
    Comments

    Adverse Events

    Time Frame Mothers were monitored for Adverse Events for up to 2 days after treatment. Infants were assessed for Adverse Events until discharge, Serious Adverse Events up to 30 days post-treatment.
    Adverse Event Reporting Description
    Arm/Group Title NAC Infant Control Infant NAC Maternal Control Maternal
    Arm/Group Description Infants treated with N-acetylcysteine Infants treated with saline Mothers of infants treated with N-acetylcysteine Mothers of infants treated with saline
    All Cause Mortality
    NAC Infant Control Infant NAC Maternal Control Maternal
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    NAC Infant Control Infant NAC Maternal Control Maternal
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 4/12 (33.3%) 3/12 (25%) 0/11 (0%) 0/11 (0%)
    General disorders
    Death 0/12 (0%) 0 1/12 (8.3%) 1 0/11 (0%) 0 0/11 (0%) 0
    Immune system disorders
    Pneumonia 1/12 (8.3%) 1 0/12 (0%) 0 0/11 (0%) 0 0/11 (0%) 0
    Culture Proven Sepsis 1/12 (8.3%) 1 1/12 (8.3%) 1 0/11 (0%) 0 0/11 (0%) 0
    Nervous system disorders
    IVH 1-2 days of age 1/12 (8.3%) 1 1/12 (8.3%) 1 0/11 (0%) 0 0/11 (0%) 0
    IVH 5-7 days of age 2/12 (16.7%) 2 0/12 (0%) 0 0/11 (0%) 0 0/11 (0%) 0
    NEC within 30 days 1/12 (8.3%) 1 1/12 (8.3%) 1 0/11 (0%) 0 0/11 (0%) 0
    Hypoxic Ischemic Encephalopathy 1/12 (8.3%) 1 0/12 (0%) 0 0/11 (0%) 0 0/11 (0%) 0
    Other (Not Including Serious) Adverse Events
    NAC Infant Control Infant NAC Maternal Control Maternal
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 5/12 (41.7%) 3/12 (25%) 2/11 (18.2%) 2/11 (18.2%)
    Blood and lymphatic system disorders
    Hypotension 0/12 (0%) 0 1/12 (8.3%) 1 1/11 (9.1%) 1 1/11 (9.1%) 1
    Prolonged PT time 5/8 (62.5%) 5 3/6 (50%) 3 0/11 (0%) 0 0/11 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Shortness of breath/wheezing 0/12 (0%) 0 0/12 (0%) 0 0/11 (0%) 0 1/11 (9.1%) 1
    Skin and subcutaneous tissue disorders
    Rash/Hives 0/12 (0%) 0 0/12 (0%) 0 1/11 (9.1%) 1 0/11 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Dorothea Jenkins
    Organization Medical University of South Carolina
    Phone 843-792-4341
    Email jenkd@musc.edu
    Responsible Party:
    Dorothea D. Jenkins, Associate Professor, Medical University of South Carolina
    ClinicalTrials.gov Identifier:
    NCT00724594
    Other Study ID Numbers:
    • R01NS052448
    • R01NS052448
    First Posted:
    Jul 29, 2008
    Last Update Posted:
    Apr 12, 2021
    Last Verified:
    Mar 1, 2021