A Randomized Trial to Prevent Congenital Cytomegalovirus (CMV) (CMV)

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Congenital Cytomegalovirus Infection; Maternal Cytomegalovirus Infection	Drug: CMV hyperimmune globulin; Other: Placebo	Phase 3

Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	800 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Prevention
Official Title:	A Randomized Trial to Prevent Congenital Cytomegalovirus (CMV)
Study Start Date :	April 2012
Estimated Primary Completion Date :	May 2018
Estimated Study Completion Date :	December 2018

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: CMV hyperimmune globulin - Cytogam®; Infusion of Cytogam®, Cytomegalovirus Immune Globulin Intravenous (Human) (CMV-IGIV)	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
Placebo Comparator: Placebo; IV 5% albumin diluted 1 to 9 with 5% Dextrose in water (D5W)	Other: Placebo; The matching placebo consists of AlbuRx® 5% diluted 1:9 with D5W. AlbuRx® 5% contains pooled adult human plasma.

Outcome Measures

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Primary Outcome Measures :

1. Composite Outcome [ Time Frame: 3 weeks of life ]
   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 Polymerase Chain Reaction (PCR) is positive but culture is negative, a repeat culture must be positive by 3 weeks of age.

Secondary Outcome Measures :

1. Gestational hypertension [ Time Frame: 42 weeks of pregnancy ]
2. Preeclampsia [ Time Frame: 42 weeks of pregnancy ]
3. Placental abruption [ Time Frame: 42 weeks of pregnancy ]
4. Gestational age at delivery [ Time Frame: 42 weeks of pregnancy ]
   Gestational age at delivery and preterm birth < 37 weeks' gestation or < 34 weeks' gestation
5. Adverse reactions and side effects [ Time Frame: Up to 42 weeks of pregnancy ]
6. Fetal and neonatal mortality [ Time Frame: 24 months ]
7. Primary outcome excluding terminations [ Time Frame: 3 weeks of life ]
8. Head circumference [ Time Frame: 3 days of life ]
   Measured within 72 hours of birth
9. Birth weight [ Time Frame: 1 day of life ]
10. Growth restriction [ Time Frame: 1 day of life ]
    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. Microcephaly [ Time Frame: 3 days of life ]
12. Symptomatic CMV infection [ Time Frame: 3 weeks of life ]
    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
13. Intraventricular hemorrhage [ Time Frame: 1 day of life ]
    Intraventricular hemorrhage (IVH) as determined by cranial ultrasounds performed as part of routine clinical care and classified based on the Papile classification system
14. Ventriculomegaly [ Time Frame: 1 day of life ]
15. Retinopathy of prematurity (ROP) [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 4 weeks ]
    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.
16. Respiratory distress syndrome [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 4 weeks ]
    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.
17. Chronic lung disease [ Time Frame: 28 days of life ]
    Chronic lung disease, or bronchopulmonary dysplasia (BPD) defined as oxygen requirement at 28 days of life.
18. Necrotizing enterocolitis (NEC) [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 4 weeks ]
    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.
19. Hyperbilirubinemia [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 4 weeks ]
    Peak total bilirubin of at least 15 mg% or the use of phototherapy
20. Neonatal infectious morbidity [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 4 weeks ]
    • Sepsis (within 72 hours and > 72 hours after birth).
    • Suspected sepsis.
    • Pneumonia.
21. Seizures / encephalopathy [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 4 weeks ]
22. Length of hospital stay [ Time Frame: participants will be followed for the duration of hospital stay, an expected average of 4 weeks ]
    Length of hospital stay, need for Neonatal Intensive Care Unit (NICU) or intermediate care admission and length of stay if admitted
23. Infant or child death [ Time Frame: 2 years of age ]
24. Sensorineural hearing loss [ Time Frame: 12 and 24 months corrected age ]
    (unilateral and bilateral)
25. Chorioretinitis [ Time Frame: 2 years of age ]
    Chorioretinitis defined by ophthalmologic exam
26. Cognitive and Motor Scores from the Bayley Certified Scales of Infant Development III [ Time Frame: 12 and 24 months corrected age ]
27. Infant/Child composite outcome [ Time Frame: 2 years of age ]

    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

Eligibility Criteria

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Ages Eligible for Study:	Child, Adult, Senior
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	Yes

Criteria

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 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

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Uma Reddy, MD, MPH	301-496-1074	Uma.Reddy@nih.gov
Contact: Elizabeth Thom, PhD	301-881-9260

Locations

United States, Alabama
University of Alabama - Birmingham	Recruiting
Birmingham, Alabama, United States, 35233
Contact: Stacy Harris, BSN 205-996-6262 stacylharris@uabmc.edu
Principal Investigator: Alan T Tita, MD
United States, California
Stanford University	Active, not recruiting
Stanford, California, United States, 94305-5317
United States, Colorado
University of Colorado Denver	Active, not recruiting
Aurora, Colorado, United States, 80045
United States, Illinois
Northwestern University	Recruiting
Chicago, Illinois, United States, 60611
Contact: Gail Mallett, BSN 312-503-3200 g-mallett@northwestern.edu
Principal Investigator: William Grobman, MD
United States, New York
Columbia University	Recruiting
New York, New York, United States, 10032
Contact: Sabine Bousleiman 212-305-4348 sb1080@columbia.edu
Principal Investigator: Cynthia Gyamfi-Bannerman, MD
United States, North Carolina
University of North Carolina - Chapel Hill	Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Kelly Clark, RN 919-350-6117 kelly_clark@med.unc.edu
Principal Investigator: John M Thorp, Jr., MD
Duke University	Recruiting
Durham, North Carolina, United States, 27710
Contact: Jennifer Ferrara, RN 919-681-6176 jennifer.ferrara@duke.edu
Principal Investigator: Geeta Swamy, MD
United States, Ohio
Case Western Reserve-Metrohealth	Recruiting
Cleveland, Ohio, United States, 44109
Contact: Wendy Dalton, RN 216-778-7533 wdalton@metrohealth.org
Principal Investigator: Edward Chien, MD
Ohio State University	Recruiting
Columbus, Ohio, United States, 43210
Contact: Anna Bartholomew, RN, BSN 614-685-3229 anna.bartholomew@osumc.edu
Principal Investigator: Catalin Buhimschi, MD
United States, Pennsylvania
Hospital of the University of Pennsylvania	Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Jennifer Craig, BSN 212-662-3926 jennifer.craig@uphs.upenn.edu
Principal Investigator: Samuel Parry, MD
Magee Womens Hospital of UPMC	Not yet recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Melissa Bickus, BSN, RN 412-641-4072 mbickus@mail.magee.edu
Principal Investigator: Hyagriv Simhan, MD
United States, Rhode Island
Brown University	Recruiting
Providence, Rhode Island, United States, 02905
Contact: Donna Allard, RNC 401-274-1122 ext 8522 dallard@wihri.org
Principal Investigator: Dwight Rouse, MD
United States, Texas
University of Texas - Southwestern Medical Center	Active, not recruiting
Dallas, Texas, United States, 75235
University of Texas - Galveston	Recruiting
Galveston, Texas, United States, 77555
Contact: Ashley Salazar, MSN 409-747-1733 assalaza@utmb.edu
Principal Investigator: George R Saade, MD
University of Texas - Houston	Recruiting
Houston, Texas, United States, 77030
Contact: Felecia Ortiz, RN 713-500-6467 Felecia.Ortiz@uth.tmc.edu
Principal Investigator: Suneet Chauhan, MD
Sub-Investigator: Baha Sibai, MD
United States, Utah
University of Utah Medical Center	Recruiting
Salt Lake City, Utah, United States, 84132
Contact: Kim Hill, RN 801-585-7645 Kim.Hill@hsc.utah.edu
Principal Investigator: Michael W Varner, MD

Sponsors and Collaborators

The George Washington University Biostatistics Center

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

Investigators

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

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	The George Washington University Biostatistics Center
ClinicalTrials.gov Identifier:	NCT01376778 History of Changes
Other Study ID Numbers:	HD36801-CMV; U10HD036801 ( U.S. NIH Grant/Contract ); U10HD027869 ( U.S. NIH Grant/Contract ); U10HD027915 ( U.S. NIH Grant/Contract ); U10HD034116 ( U.S. NIH Grant/Contract ); U10HD034208 ( U.S. NIH Grant/Contract ); U10HD040500 ( U.S. NIH Grant/Contract ); U10HD040485 ( U.S. NIH Grant/Contract ); U10HD040544 ( U.S. NIH Grant/Contract ); U10HD040545 ( U.S. NIH Grant/Contract ); U10HD040560 ( U.S. NIH Grant/Contract ); U10HD040512 ( U.S. NIH Grant/Contract ); U10HD053097 ( U.S. NIH Grant/Contract ); U10HD068282 ( U.S. NIH Grant/Contract ); U10HD068258 ( U.S. NIH Grant/Contract ); U10HD068268 ( U.S. NIH Grant/Contract )
First Posted:	June 20, 2011
Last Update Posted:	July 21, 2017
Last Verified:	July 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
Plan Description:	The dataset will be shared per NIH policy after the completion and publication of the main analyses. Requests for datasets can be sent to mfmudatasets@bsc.gwu.edu.

Keywords provided by The George Washington University Biostatistics Center:

Perinatology; Cytomegalovirus immune globulin; Cytogam; CMVIG infusions

Additional relevant MeSH terms:

Infection; Communicable Diseases; Cytomegalovirus Infections	Herpesviridae Infections; DNA Virus Infections; Virus Diseases