A Randomized Trial to Prevent Congenital Cytomegalovirus (CMV)

This study is currently recruiting participants.
Verified November 2013 by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Sponsor:
Information provided by (Responsible Party):
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier:
NCT01376778
First received: June 15, 2011
Last updated: November 15, 2013
Last verified: November 2013

June 15, 2011
November 15, 2013
April 2012
May 2018   (final data collection date for primary outcome measure)
Composite Outcome [ Time Frame: 3 weeks of life ] [ Designated as safety issue: No ]
The primary outcome is defined as fetal loss (spontaneous or termination), confirmed fetal CMV infection from amniocentesis, neonatal death before assessment of CMV infection can be made, or neonatal congenital CMV infection. Neonatal congenital CMV infection is diagnosed by urine or saliva collected by 3 weeks of age that is positive for CMV by culture (the intent will be to obtain in the first two days of life). In the event that PCR is positive but culture is negative, a repeat culture must be positive by 3 weeks of age.
Same as current
Complete list of historical versions of study NCT01376778 on ClinicalTrials.gov Archive Site
  • Gestational hypertension [ Time Frame: 42 weeks of pregnancy ] [ Designated as safety issue: No ]
  • Preeclampsia [ Time Frame: 42 weeks of pregnancy ] [ Designated as safety issue: No ]
  • Placental abruption [ Time Frame: 42 weeks of pregnancy ] [ Designated as safety issue: No ]
  • Gestational age at delivery [ Time Frame: 42 weeks of pregnancy ] [ Designated as safety issue: No ]
    Gestational age at delivery and preterm birth < 37 weeks' gestation or < 34 weeks' gestation
  • Adverse reactions and side effects [ Time Frame: Up to 42 weeks of pregnancy ] [ Designated as safety issue: Yes ]
  • Fetal and neonatal mortality [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  • Primary outcome excluding terminations [ Time Frame: 3 weeks of life ] [ Designated as safety issue: No ]
  • Head circumference [ Time Frame: 3 days of life ] [ Designated as safety issue: No ]
    Measured within 72 hours of birth
  • Birth weight [ Time Frame: 1 day of life ] [ Designated as safety issue: No ]
  • Growth restriction [ Time Frame: 1 day of life ] [ Designated as safety issue: No ]
    Growth restriction defined as <5th percentile weight for gestational age, assessed specifically by sex and race of the infant based on United States birth certificate data
  • Microcephaly [ Time Frame: 3 days of life ] [ Designated as safety issue: No ]
  • Symptomatic CMV infection [ Time Frame: 3 weeks of life ] [ Designated as safety issue: No ]
    Symptomatic CMV infection defined as CMV isolated from an amniocentesis, or urine or saliva during the first three weeks of life and at least one of the following: jaundice, hepatomegaly, splenomegaly, growth restriction, failure to thrive, intracerebral calcifications, microcephaly, hypotonia, seizures, petechial rash, hearing loss, interstitial pneumonitis, thrombocytopenia, anemia, hepatitis, chorioretinitis, or CMV in cerebrospinal fluid
  • Intraventricular hemorrhage [ Time Frame: 1 day of life ] [ Designated as safety issue: No ]
    Intraventricular hemorrhage (IVH) as determined by cranial ultrasounds performed as part of routine clinical care and classified based on the Papile classification system
  • Ventriculomegaly [ Time Frame: 1 day of life ] [ Designated as safety issue: No ]
  • Retinopathy of prematurity (ROP) [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 4 weeks ] [ Designated as safety issue: No ]
    This diagnosis will be reached when an ophthalmologic examination of the retina has been performed and retinopathy of prematurity (ROP) is diagnosed at Stage I (demarcation line in the retina) or greater.
  • Respiratory distress syndrome [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 4 weeks ] [ Designated as safety issue: No ]
    Respiratory distress syndrome (RDS) defined as the presence of clinical signs of respiratory distress (tachypnea, retractions, flaring, grunting, or cyanosis), with an oxygen requirement and a chest x-ray that shows hypoventilation and reticulogranular infiltrates.
  • Chronic lung disease [ Time Frame: 28 days of life ] [ Designated as safety issue: No ]
    Chronic lung disease, or bronchopulmonary dysplasia (BPD) defined as oxygen requirement at 28 days of life.
  • Necrotizing enterocolitis (NEC) [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 4 weeks ] [ Designated as safety issue: No ]
    Necrotizing enterocolitis (NEC), defined as modified Bell Stage 2 or 3. Stage 2: Clinical signs and symptoms with pneumatosis intestinalis on radiographs. Stage 3: Advanced clinical signs and symptoms, pneumatosis, impending or proven intestinal perforation.
  • Hyperbilirubinemia [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 4 weeks ] [ Designated as safety issue: No ]
    Peak total bilirubin of at least 15 mg% or the use of phototherapy
  • Neonatal infectious morbidity [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 4 weeks ] [ Designated as safety issue: No ]
    • Sepsis (within 72 hours and > 72 hours after birth).
    • Suspected sepsis.
    • Pneumonia.
  • Seizures / encephalopathy [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 4 weeks ] [ Designated as safety issue: No ]
  • Length of hospital stay [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 4 weeks ] [ Designated as safety issue: No ]
    Length of hospital stay, need for NICU or intermediate care admission and length of stay if admitted
  • Infant or child death [ Time Frame: 2 years of age ] [ Designated as safety issue: No ]
  • Sensorineural hearing loss [ Time Frame: 12 and 24 months corrected age ] [ Designated as safety issue: No ]
    (unilateral and bilateral)
  • Chorioretinitis [ Time Frame: 2 years of age ] [ Designated as safety issue: No ]
    Chorioretinitis defined by ophthalmologic exam
  • Cognitive and Motor Scores from the Bayley Certified Scales of Infant Development III [ Time Frame: 12 and 24 months corrected age ] [ Designated as safety issue: No ]
  • Infant/Child composite outcome [ Time Frame: 2 years of age ] [ Designated as safety issue: No ]

    Composite outcome at 24 months including any of the following attributable to congenital CMV infection:

    • Sensorineural hearing loss (unilateral and bilateral)
    • Developmental delay defined as Cognitive score < 70 or Motor score < 70 on the Bayley III
    • Chorioretinitis
    • Fetal loss or death of neonate, infant or child
  • Gestational hypertension [ Time Frame: 42 weeks of pregnancy ] [ Designated as safety issue: No ]
  • Preeclampsia [ Time Frame: 42 weeks of pregnancy ] [ Designated as safety issue: No ]
  • Placental abruption [ Time Frame: 42 weeks of pregnancy ] [ Designated as safety issue: No ]
  • Gestational age at delivery [ Time Frame: 42 weeks of pregnancy ] [ Designated as safety issue: No ]
    Gestational age at delivery and preterm birth < 37 weeks' gestation or < 34 weeks' gestation
  • Adverse reactions and side effects [ Time Frame: Up to 42 weeks of pregnancy ] [ Designated as safety issue: Yes ]
  • Fetal and neonatal mortality [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  • Primary outcome excluding terminations [ Time Frame: 3 weeks of life ] [ Designated as safety issue: No ]
  • Head circumference [ Time Frame: 3 days of life ] [ Designated as safety issue: No ]
    Measured within 72 hours of birth
  • Birth weight [ Time Frame: 1 day of life ] [ Designated as safety issue: No ]
  • Growth restriction [ Time Frame: 1 day of life ] [ Designated as safety issue: No ]
    Growth restriction defined as <5th percentile weight for gestational age, assessed specifically by sex and race of the infant based on United States birth certificate data
  • Microcephaly [ Time Frame: 3 days of life ] [ Designated as safety issue: No ]
  • Symptomatic CMV infection [ Time Frame: 3 weeks of life ] [ Designated as safety issue: No ]
    Symptomatic CMV infection defined as CMV isolated from an amniocentesis, or urine or saliva during the first three weeks of life and at least one of the following: jaundice, hepatomegaly, splenomegaly, growth restriction, failure to thrive, intracerebral calcifications, microcephaly, hypotonia, seizures, petechial rash, hearing loss, interstitial pneumonitis, thrombocytopenia, anemia, hepatitis, chorioretinitis, or CMV in cerebrospinal fluid
  • Intraventricular hemorrhage [ Time Frame: 1 day of life ] [ Designated as safety issue: No ]
    Intraventricular hemorrhage (IVH) as determined by cranial ultrasounds performed as part of routine clinical care and classified based on the Papile classification system
  • Ventriculomegaly [ Time Frame: 1 day of life ] [ Designated as safety issue: No ]
  • Retinopathy of prematurity [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 4 weeks ] [ Designated as safety issue: No ]
    This diagnosis will be reached when an ophthalmologic examination of the retina has been performed and ROP is diagnosed at Stage I (demarcation line in the retina) or greater.
  • Respiratory distress syndrome [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 4 weeks ] [ Designated as safety issue: No ]
    Respiratory distress syndrome (RDS) defined as the presence of clinical signs of respiratory distress (tachypnea, retractions, flaring, grunting, or cyanosis), with an oxygen requirement and a chest x-ray that shows hypoaeration and reticulogranular infiltrates.
  • Chronic lung disease [ Time Frame: 28 days of life ] [ Designated as safety issue: No ]
    Chronic lung disease (BPD) defined as oxygen requirement at 28 days of life.
  • Necrotizing enterocolitis [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 4 weeks ] [ Designated as safety issue: No ]
    NEC, defined as modified Bell Stage 2 or 3. Stage 2: Clinical signs and symptoms with pneumatosis intestinalis on radiographs. Stage 3: Advanced clinical signs and symptoms, pneumatosis, impending or proven intestinal perforation.
  • Hyperbilirubinemia [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 4 weeks ] [ Designated as safety issue: No ]
    Peak total bilirubin of at least 15 mg% or the use of phototherapy
  • Neonatal infectious morbidity [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 4 weeks ] [ Designated as safety issue: No ]
    • Sepsis (within 72 hours and > 72 hours after birth).
    • Suspected sepsis.
    • Pneumonia.
  • Seizures / encephalopathy [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 4 weeks ] [ Designated as safety issue: No ]
  • Length of hospital stay [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 4 weeks ] [ Designated as safety issue: No ]
    Length of hospital stay, need for NICU or intermediate care admission and length of stay if admitted
  • Infant or child death [ Time Frame: 2 years of age ] [ Designated as safety issue: No ]
  • Sensorineural hearing loss [ Time Frame: 12 and 24 months corrected age ] [ Designated as safety issue: No ]
    (unilateral and bilateral)
  • Chorioretinitis [ Time Frame: 2 years of age ] [ Designated as safety issue: No ]
    Chorioretinitis defined by ophthalmologic exam
  • Cognitive and Motor Scores from the Bayley Certified Scales of Infant Development III [ Time Frame: 12 and 24 months corrected age ] [ Designated as safety issue: No ]
  • Infant/Child composite outcome [ Time Frame: 2 years of age ] [ Designated as safety issue: No ]

    Composite outcome at 24 months including any of the following attributable to congenital CMV infection:

    • Sensorineural hearing loss (unilateral and bilateral)
    • Developmental delay defined as Cognitive score < 70 or Motor score < 70 on the Bayley III
    • Chorioretinitis
    • Fetal loss or death of neonate, infant or child
Not Provided
Not Provided
 
A Randomized Trial to Prevent Congenital Cytomegalovirus (CMV)
A Randomized Trial to Prevent Congenital Cytomegalovirus (CMV)

Cytomegalovirus (CMV) is a common virus that usually presents with few if any side effects. When first infected, some people may have symptoms similar to mononucleosis (i.e., fatigue, weakness, fever, swollen glands). Most people in the United States are infected during childhood or as adults if they work around children. Pregnant women, who have not been infected with CMV in the past and become infected during pregnancy (i.e. a primary infection), may cause their babies to get infected with CMV. Babies that are infected may develop permanent disabilities including hearing loss and a small portion will die from the infection.

Currently it is not routine practice to screen pregnant women for CMV infection. Additionally, there is no agreement about how to evaluate and manage pregnant women infected with CMV for the first time. There is also no evidence that treatment is beneficial for the baby.

The purpose of this research study is to determine whether treating pregnant women who have a primary CMV infection with CMV antibodies will reduce the number of babies infected with CMV.

Cytomegalovirus (CMV) is the most common congenital infection, with approximately 44,000 congenitally infected infants in the U.S. per year. A substantial proportion of these infants will die or suffer permanent injury as a result of their infection. The severity of congenital infection is greatest with primary maternal CMV infection. Currently, there is no proven method of preventing congenital CMV infection, and the approach to primary maternal CMV infection in the United States is haphazard and ineffective. One small, non-randomized study suggests that maternal administration of CMV hyperimmune globulin may significantly reduce the rate of congenital CMV infection following maternal primary infection. The MFMU CMV Trial will address the primary research question: does maternal administration of CMV hyperimmune globulin lower the rate of congenital CMV infection among the offspring of women who have been diagnosed with primary CMV infection during early pregnancy?

The research study is funded by the Eunice Kennedy Shriver National Institutes of Child Health and Human Development (NICHD). Fourteen medical centers across the country are participating in this research study. In all, 800 pregnant women who are identified with a primary CMV infection will be enrolled in this research study. The children of these women will be evaluated and tested at one and two years of age.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Prevention
  • Congenital Cytomegalovirus Infection
  • Maternal Cytomegalovirus Infection
Drug: CMV hyperimmune globulin
The study's active drug is Cytogam® which is an immunoglobulin G (IgG) containing a standardized amount of antibody to CMV. This drug contains pooled adult human plasma selected for high titers of antibody for CMV, and is administered intravenously at a dose of 100 mg/kg body weight.
Other Names:
  • CMV-IGIV
  • Cytogam
  • Active Comparator: Cytogam
    Infusion of Cytogam®, Cytomegalovirus Immune Globulin Intravenous (Human) (CMV-IGIV)
    Intervention: Drug: CMV hyperimmune globulin
  • Placebo Comparator: Placebo
    IV 5% albumin diluted 1 to 9 with D5W
    Intervention: Drug: CMV hyperimmune globulin
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
800
December 2018
May 2018   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Diagnosis of primary maternal CMV infection on the basis of one of the following:

    1. A positive CMV Immunoglobulin M (IgM) antibody and low-avidity maternal CMV Immunoglobulin G (IgG) antibody screen
    2. Evidence of maternal seroconversion with development of CMV IgG antibody following a prior negative CMV screen
  • Gestational age at randomization no later than 23 weeks 6 days based on clinical information and evaluation of the earliest ultrasound; or no later than 27 weeks 6 days for women with a positive IgM, negative IgG initially screened before 23 weeks who are rescreened after 2-4 weeks and have evidence of IgG seroconversion.
  • Singleton pregnancy. A twin pregnancy reduced to singleton (either spontaneously or therapeutically) before 14 weeks by project gestational age is acceptable.

Exclusion Criteria:

  • Maternal CMV infection pre-dating pregnancy as defined by a high IgG avidity index or a positive IgG in the presence of a negative IgM.
  • Known hypersensitivity to plasma or plasma derived products
  • Planned termination of pregnancy
  • Known major fetal anomalies or demise
  • Maternal IgA deficiency
  • Planned use of immune globulin, ganciclovir, or valganciclovir
  • Maternal renal disease (most recent pre-randomization serum creatinine ≥ 1.4 mg/dL; all women must have serum creatinine measured during the pregnancy and prior to randomization)
  • Maternal immune impairment (e.g., HIV infection, organ transplant on anti-rejection medications)
  • Findings on pre-randomization ultrasound suggestive of established fetal CMV infection (cerebral ventriculomegaly, microcephaly, cerebral or intra-abdominal calcifications, abnormalities of amniotic fluid volume, echogenic bowel or ascites). Abnormally low amniotic fluid volume is defined as no fluid prior to 14 weeks or maximum vertical pocket < 2 cm on or after 14 weeks gestation. Abnormally high amniotic fluid volume is defined as > 10 cm.
  • Positive fetal CMV findings from culture (amniotic fluid) or PCR.
  • Congenital infection with rubella, syphilis, varicella, parvovirus or toxoplasmosis diagnosed by serology and ultrasound or amniotic fluid testing.
  • Intention of the patient or of the managing obstetricians for the delivery to be outside a Maternal-Fetal Medicine Units Network (MFMU) Network center
  • Participation in another interventional study that influences fetal or neonatal death
  • Unwilling or unable to commit to 2 year follow-up of the infant
Female
Not Provided
Yes
Contact: Uma Reddy, MD, MPH 301-496-1074 Uma.Reddy@nih.gov
Contact: Elizabeth Thom, PhD 301-881-9260
United States
 
NCT01376778
HD36801-CMV, U01HD036801
Yes
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Not Provided
Study Director: Uma Reddy, MD, MPH Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Principal Investigator: Elizabeth Thom, PhD George Washington University
Study Chair: Brenna Anderson, MD Brown University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
November 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP