A Randomized Trial to Prevent Congenital Cytomegalovirus (CMV) (CMV)
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT01376778 |
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Recruitment Status :
Completed
First Posted : June 20, 2011
Results First Posted : February 2, 2023
Last Update Posted : February 2, 2023
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Sponsor:
The George Washington University Biostatistics Center
Collaborator:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
The George Washington University Biostatistics Center
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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 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 399 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 |
| Actual Primary Completion Date : | October 2019 |
| Actual Study Completion Date : | June 30, 2021 |
Resource links provided by the National Library of Medicine
MedlinePlus related topics:
Cytomegalovirus Infections
Drug Information available for:
Cytotect
| Arm | Intervention/treatment |
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Active Comparator: CMV hyperimmune globulin - Cytogam®
Infusion of Cytogam®, Cytomegalovirus Immune Globulin Intravenous (Human) (CMV-IGIV)
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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:
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Placebo Comparator: Placebo
IV 5% albumin diluted 1 to 9 with 5% Dextrose in water (D5W)
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Other: Placebo
The matching placebo consists of AlbuRx® 5% diluted 1:9 with D5W. AlbuRx® 5% contains pooled adult human plasma. |
Primary Outcome Measures :
- 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.
- 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
- 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
- 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
- Number of Participants With Fetal Death Without Proven CMV Infection [ Time Frame: From randomization through delivery ]component of primary composite outcome
Secondary Outcome Measures :
- 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
- 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
- Median Gestational Age at Delivery [ Time Frame: Delivery ]Gestational age at delivery in weeks
- 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
- 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
- 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
- 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
- Median Neonatal Head Circumference [ Time Frame: 72 hours postpartum ]Neonatal head circumference measured within 72 hours of birth
- Median Birth Weight [ Time Frame: Delivery ]Birth weight as recorded in the medical record
- 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)
- 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
- 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
- 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
- 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.
- 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).
- 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
- 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.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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.
- 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.
- 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
- 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
- Failure to Thrive at 24 Months [ Time Frame: 24 months of age ]Failure to thrive defined as <10th percentile for weight at 24 months
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| Ages Eligible for Study: | Child, Adult, Older Adult |
| Sexes Eligible for Study: | Female |
| Accepts Healthy Volunteers: | Yes |
Criteria
Inclusion Criteria:
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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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01376778
Locations
| United States, Alabama | |
| University of Alabama - Birmingham | |
| Birmingham, Alabama, United States, 35233 | |
| United States, California | |
| Stanford University | |
| Stanford, California, United States, 94305-5317 | |
| United States, Colorado | |
| University of Colorado Denver | |
| Aurora, Colorado, United States, 80045 | |
| United States, Illinois | |
| Northwestern University | |
| Chicago, Illinois, United States, 60611 | |
| United States, New York | |
| Columbia University | |
| New York, New York, United States, 10032 | |
| United States, North Carolina | |
| University of North Carolina - Chapel Hill | |
| Chapel Hill, North Carolina, United States, 27599 | |
| Duke University | |
| Durham, North Carolina, United States, 27710 | |
| United States, Ohio | |
| Case Western Reserve-Metrohealth | |
| Cleveland, Ohio, United States, 44109 | |
| Ohio State University | |
| Columbus, Ohio, United States, 43210 | |
| United States, Pennsylvania | |
| Hospital of the University of Pennsylvania | |
| Philadelphia, Pennsylvania, United States, 19104 | |
| Magee Womens Hospital of UPMC | |
| Pittsburgh, Pennsylvania, United States, 15213 | |
| United States, Rhode Island | |
| Brown University | |
| Providence, Rhode Island, United States, 02905 | |
| United States, Texas | |
| University of Texas - Southwestern Medical Center | |
| Dallas, Texas, United States, 75235 | |
| University of Texas - Galveston | |
| Galveston, Texas, United States, 77555 | |
| University of Texas - Houston | |
| Houston, Texas, United States, 77030 | |
| United States, Utah | |
| University of Utah Medical Center | |
| Salt Lake City, Utah, United States, 84132 | |
Sponsors and Collaborators
The George Washington University Biostatistics Center
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
| Study Director: | Monica Longo, MD | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | |
| Principal Investigator: | Rebecca Clifton, PhD | George Washington University | |
| Study Chair: | Brenna Hughes, MD | Brown University |
Study Documents (Full-Text)
Documents provided by The George Washington University Biostatistics Center:
Documents provided by The George Washington University Biostatistics Center:
Study Protocol, Statistical Analysis Plan, and Informed Consent Form [PDF] November 1, 2017
Publications of Results:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Keywords provided by The George Washington University Biostatistics Center:
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Perinatology Cytomegalovirus immune globulin Cytogam CMVIG infusions |
Additional relevant MeSH terms:
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Infections Communicable Diseases Cytomegalovirus Infections Disease Attributes |
Pathologic Processes Herpesviridae Infections DNA Virus Infections Virus Diseases |