Safety of N-acetylcysteine in Maternal Chorioamnionitis (NAC in Chorio)
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
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:
|
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:
|
Outcome Measures
Primary Outcome Measures
- NAC Terminal Elimination Half-life [prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion]
- NAC Volume of Distribution [prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion]
- NAC Total Body Clearance [prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion]
- NAC Concentrations [Peak: 30 minutes after NAC infusion. Cord: at delivery]
- Placental Transfer Ratio [At time of delivery]
Ratio of NAC concentration in cord to maternal venous blood
- 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]
- Cerebral Blood Flow [after NAC infusion]
Resistive index in middle cerebral artery (MCA)
- Prothrombin Time [after N-acetylcystiene or saline infusion]
prothrombin clotting time
Secondary Outcome Measures
- Magnetic Resonance Spectroscopy of Infants [36 - 40 weeks gestational age]
ratio of myoInositol / NAA concentrations in basal ganglia
- Cytokine Level IL-1Ra in Plasma [after N-acetylcysteine infusion]
anti-inflammatory cytokine Interleukin -1 Receptor alpha (IL-1Ra)
Eligibility Criteria
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
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.- R01NS052448
- R01NS052448
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
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)
|
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)
|
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)
|
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)
|
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)
|
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)
|
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 |
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 |
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 |
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
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 |
jenkd@musc.edu |
- R01NS052448
- R01NS052448