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NCT Number: NCT01376778

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.

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Key information

Conditions

Congenital Cytomegalovirus Infection Cytomegalovirus Infections DNA Virus Infections Herpesviridae Infections Infections Maternal Cytomegalovirus Infection Virus Diseases

Sex eligibility

Female

Study type

Interventional

Phase

Phase 3

Primary location

University of Alabama - Birmingham, Birmingham, Alabama, United States

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About this study

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). Sixteen 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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Diagnosis of primary maternal CMV infection on the basis of one of the following:
  • A positive CMV Immunoglobulin M (IgM) antibody and low-avidity maternal CMV Immunoglobulin G (IgG) antibody screen
  • 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 Immunoglobulin A (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

Treatment and study plan

CMV hyperimmune globulin

Drug

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

Placebo

Other

The matching placebo consists of AlbuRx® 5% diluted 1:9 with D5W. AlbuRx® 5% contains pooled adult human plasma.

Primary outcomes

  1. Number of Participants With the Composite Primary Outcome

    Time frame: From randomization through 3 weeks of life

    The primary outcome is a binary outcome defined by the occurrence or non-occurrence of any of the following vs. none of the following: 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 Polymerase Chain Reaction (PCR) is positive but culture is negative, a repeat culture must be positive by 3 weeks of age.

  2. Number of Participants Who Had a Fetus or Neonate With CMV Infection

    Time frame: From randomization through 3 weeks of life

    Component of composite primary outcome

  3. Number of Participants Who Had a Neonatal Death Without CMV Infection

    Time frame: From randomization through 3 weeks of life

    component of composite primary outcome

  4. Number of Participants With a Fetal or Neonatal Death With Proven CMV Infection

    Time frame: From randomization through 3 weeks of life

    component of primary composite outcome

  5. Number of Participants With Fetal Death Without Proven CMV Infection

    Time frame: From randomization through delivery

    component of primary composite outcome

Secondary outcomes

  1. Number of Participants With Gestational Hypertension or Preeclampsia

    Time frame: from randomization through discharge from the hospital

    Gestational hypertension or preeclampsia is a binary outcome defined by occurrence or non-occurrence of gestational hypertension or preeclampsia. Gestational hypertension or preeclampsia are new onset hypertension during pregnancy

  2. Number of Participants With Placental Abruption

    Time frame: From randomization through delivery (maximum 42 weeks gestation)

    Placental abruption is a binary outcome defined by occurrence or non-occurrence of placental abruption, defined as bleeding and contraction pain

  3. Median Gestational Age at Delivery

    Time frame: Delivery

    Gestational age at delivery in weeks

  4. Number of Participants Whose Gestational Age at Delivery Was Before 37 Weeks

    Time frame: Delivery before 37 weeks gestation

    Gestational age before 37 weeks gestation is a binary outcome meaning occurrence or non-occurrence of delivery before 37 weeks gestation

  5. Number of Participants Whose Gestational Age at Delivery Was Before 34 Weeks, 0 Days

    Time frame: Delivery before 34 weeks gestation

    Gestational age before 34 weeks, 0 days gestation is a binary outcome meaning occurrence or non-occurrence of delivery before 34 weeks gestation

  6. Number of Participants Reporting Yes or no to Medication Side Effects

    Time frame: From randomization (10-27 weeks gestation) through delivery (maximum 42 weeks gestation)

    Occurrence or non-occurrence of a designated side effect of medication

  7. Number of Participants Who Had a Fetal or Neonatal Death

    Time frame: From randomization (10-27 weeks gestation) through delivery (maximum 42 weeks gestation) up to 120 days of life

    Fetal death or death of a neonate born alive

  8. Median Neonatal Head Circumference

    Time frame: 72 hours postpartum

    Neonatal head circumference measured within 72 hours of birth

  9. Median Birth Weight

    Time frame: Delivery

    Birth weight as recorded in the medical record

  10. Number of Participants With Fetal Growth Restriction

    Time frame: Delivery

    Fetal growth restriction is a binary outcome defined as the occurrence or non-occurrence of 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)

  11. Number of Participants With Symptomatic CMV Infection

    Time frame: During pregnancy up to 3 weeks postpartum

    Fetal or neonatal symptomatic CMV infection is a binary outcome defined as the occurrence or non-occurrence of 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 (with direct bilirubin exceeding 20% of total bilirubin), thrombocytopenia , anemia , hepatitis, 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

  12. Number of Neonates With Grade 3 or 4 Intraventricular Hemorrhage

    Time frame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner

    Intraventricular hemorrhage (IVH) as determined by cranial ultrasounds performed as part of routine clinical care and classified based on the Papile classification system. IVH is a binary outcome defined by occurrence or non-occurrence of IVH

  13. Number of Neonates With Ventriculomegaly

    Time frame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner

    Ventriculomegaly is a binary outcome defined by the occurrence or non-occurrence of ventriculomegaly

  14. Number of Neonates With Retinopathy of Prematurity (ROP)

    Time frame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner

    Retinopathy of prematurity is a binary outcome defined by the occurrence or non-occurrence of retinopathy of prematurity, diagnosed by ophthalmologic examination of the retina and a diagnosis of Stage I (demarcation line in the retina) or greater.

  15. Number of Neonates With Respiratory Distress Syndrome

    Time frame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner

    Respiratory distress syndrome is a binary outcome defined by the occurrence or non-occurrence of Respiratory distress syndrome (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).

  16. Number of Neonates With Chronic Lung Disease

    Time frame: 28 days of life

    Neonatal chronic lung disease is a binary outcome defined by the occurrence or non-occurrence of chronic lung disease or bronchopulmonary dysplasia (BPD) defined as oxygen requirement at 28 days of life

  17. Number of Neonates With Necrotizing Enterocolitis (NEC)

    Time frame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner

    Necrotizing enterocolitis (NEC) is a binary outcome defined by the occurrence or non-occurrence of 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.

  18. Number of Neonates With Hyperbilirubinemia

    Time frame: From birth to 1 week of life

    Hyperbilirubinemia is a binary outcome defined by the occurrence or non-occurrence of hyperbilirubinemia. Peak total bilirubin of at least 15 mg% or the use of phototherapy

  19. Number of Neonates With Suspected Neonatal Sepsis

    Time frame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner

    Suspected neonatal sepsis is a binary outcome defined as the occurrence or non-occurrence of suspected neonatal sepsis

  20. Number of Neonates With Neonatal Pneumonia

    Time frame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner

    Neonatal pneumonia is a binary outcome defined as the occurrence or non-occurrence of neonatal pneumonia

  21. Number of Neonates Experiencing Seizures / Encephalopathy

    Time frame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner

    Neonatal seizures/encephalopathy is a binary outcome defined as the occurrence or non-occurrence of seizures/encephalopathy

  22. Median Length of Neonatal Hospital Stay

    Time frame: birth to neonatal hospital discharge (usually a maximum of 120 days)

    Length of hospital stay, need for Neonatal Intensive Care Unit (NICU) or intermediate care admission and length of stay if admitted

  23. Number of Participants Experiencing Infant or Child Death

    Time frame: Birth to 24 month study exam

    Death of infant or child before the 24 month study exam

  24. Number of Children With Sensorineural Hearing Loss

    Time frame: 12 and 24 months corrected age

    Sensorineural hearing loss is defined as the occurrence or non-occurrence of sensorineural hearing loss defined as unilateral and bilateral sensorineural hearing loss

  25. Number of Children Diagnosed With Chorioretinitis

    Time frame: 2 years of age

    Chorioretinitis is defined as the occurrence or non-occurrence of chorioretinitis defined by ophthalmologic exam

  26. Mean Cognitive Composite Scores From the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III)

    Time frame: 12 and 24 months corrected age

    The Bayley Scales of Infant and Toddler Development® | Third Edition (Bayley®-III), is a comprehensive tool to identify development issues during early childhood. The Bayley-III Cognitive Scale subtests assess cognitive function through the use of memory, problem solving and manipulation subtests. Scores on individual Cognitive subtests range from 1 (worst outcome) to 19 (better outcome) (Mean 10, SD 3). Individual subtest scores between 8 and 12 are considered average. The raw scores on the subtests are converted to scaled scores based on American norms by age. Cognitive Scale composite scores range from 55 (low, worse outcome) to 155 (high, better outcome) (mean 100; SD 15). Severe disability was defined as a composite score <70.

  27. Mean Motor Composite Scores From the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III)

    Time frame: 12 and 24 months corrected age

    The Bayley Scales of Infant and Toddler Development® | Third Edition (Bayley®-III), is a comprehensive tool to identify development issues during early childhood. The Bayley-III Motor Scale subtests assess motor function through fine motor and gross motor subtests. Scores on individual Motor subtests range from 1 (worst outcome) to 19 (better outcome) (Mean 10, SD 3). Individual subtest scores between 8 and 12 are considered average. The raw scores on the subtests are converted to scaled scores based on American norms by age. Motor Scale composite scores range from 55 (low, worse outcome) to 155 (high, better outcome) (mean 100; SD 15). Severe disability was defined as a composite score <70.

  28. Number of Infants or Children With the Composite Outcome

    Time frame: 24 month study exam

    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

  29. Overall Child Status at 24 Months of Age

    Time frame: 24 month study exam

    Child status at age 24 months, classified as: • Fetal loss or death of neonate, infant or child • Congenital CMV infection with severe disability • Congenital CMV infection without severe disability • Infant not infected with CMV

  30. Failure to Thrive at 24 Months

    Time frame: 24 months of age

    Failure to thrive defined as <10th percentile for weight at 24 months

Sponsors and collaborators

Lead sponsor

The George Washington University Biostatistics Center

Other

Collaborators

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Registry information

Acronym: CMV

Important dates

Study start
2012
Primary completion
2019
Study completion
2021
First posted
Jun 20, 2011
Registry last updated
Feb 2, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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