A Randomized Trial to Prevent Congenital Cytomegalovirus (CMV)

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Congenital Cytomegalovirus Infection, Maternal Cytomegalovirus Infection

Intervention / Treatment
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* Drug: CMV hyperimmune globulin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With the Composite Primary Outcome | 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. | From randomization through 3 weeks of life | 
| Number of Participants Who Had a Fetus or Neonate With CMV Infection | Component of composite primary outcome | From randomization through 3 weeks of life | 
| Number of Participants Who Had a Neonatal Death Without CMV Infection | component of composite primary outcome | From randomization through 3 weeks of life | 
| Number of Participants With a Fetal or Neonatal Death With Proven CMV Infection | component of primary composite outcome | From randomization through 3 weeks of life | 
| Number of Participants With Fetal Death Without Proven CMV Infection | component of primary composite outcome | From randomization through delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Gestational Hypertension or Preeclampsia | 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 | from randomization through discharge from the hospital | 
| Number of Participants With Placental Abruption | Placental abruption is a binary outcome defined by occurrence or non-occurrence of placental abruption, defined as bleeding and contraction pain | From randomization through delivery (maximum 42 weeks gestation) | 
| Median Gestational Age at Delivery | Gestational age at delivery in weeks | Delivery | 
| Number of Participants Whose Gestational Age at Delivery Was Before 37 Weeks | Gestational age before 37 weeks gestation is a binary outcome meaning occurrence or non-occurrence of delivery before 37 weeks gestation | Delivery before 37 weeks gestation | 
| Number of Participants Whose Gestational Age at Delivery Was Before 34 Weeks, 0 Days | Gestational age before 34 weeks, 0 days gestation is a binary outcome meaning occurrence or non-occurrence of delivery before 34 weeks gestation | Delivery before 34 weeks gestation | 
| Number of Participants Reporting Yes or no to Medication Side Effects | Occurrence or non-occurrence of a designated side effect of medication | From randomization (10-27 weeks gestation) through delivery (maximum 42 weeks gestation) | 
| Number of Participants Who Had a Fetal or Neonatal Death | Fetal death or death of a neonate born alive | From randomization (10-27 weeks gestation) through delivery (maximum 42 weeks gestation) up to 120 days of life | 
| Median Neonatal Head Circumference | Neonatal head circumference measured within 72 hours of birth | 72 hours postpartum | 
| Median Birth Weight | Birth weight as recorded in the medical record | Delivery | 
| Number of Participants With Fetal Growth Restriction | 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) | Delivery | 
| Number of Participants With Symptomatic CMV Infection | 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 | During pregnancy up to 3 weeks postpartum | 
| Number of Neonates With Grade 3 or 4 Intraventricular Hemorrhage | 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 | 0 days to approximately 120 days of life or hospital discharge, whichever is sooner | 
| Number of Neonates With Ventriculomegaly | Ventriculomegaly is a binary outcome defined by the occurrence or non-occurrence of ventriculomegaly | 0 days to approximately 120 days of life or hospital discharge, whichever is sooner | 
| Number of Neonates With Retinopathy of Prematurity (ROP) | 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. | 0 days to approximately 120 days of life or hospital discharge, whichever is sooner | 
| Number of Neonates With Respiratory Distress Syndrome | 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). | 0 days to approximately 120 days of life or hospital discharge, whichever is sooner | 
| Number of Neonates With Chronic Lung Disease | 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 | 28 days of life | 
| Number of Neonates With Necrotizing Enterocolitis (NEC) | 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. | 0 days to approximately 120 days of life or hospital discharge, whichever is sooner | 
| Number of Neonates With Hyperbilirubinemia | 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 | From birth to 1 week of life | 
| Number of Neonates With Suspected Neonatal Sepsis | Suspected neonatal sepsis is a binary outcome defined as the occurrence or non-occurrence of suspected neonatal sepsis | 0 days to approximately 120 days of life or hospital discharge, whichever is sooner | 
| Number of Neonates With Neonatal Pneumonia | Neonatal pneumonia is a binary outcome defined as the occurrence or non-occurrence of neonatal pneumonia | 0 days to approximately 120 days of life or hospital discharge, whichever is sooner | 
| Number of Neonates Experiencing Seizures / Encephalopathy | Neonatal seizures/encephalopathy is a binary outcome defined as the occurrence or non-occurrence of seizures/encephalopathy | 0 days to approximately 120 days of life or hospital discharge, whichever is sooner | 
| Median Length of Neonatal Hospital Stay | Length of hospital stay, need for Neonatal Intensive Care Unit (NICU) or intermediate care admission and length of stay if admitted | birth to neonatal hospital discharge (usually a maximum of 120 days) | 
| Number of Participants Experiencing Infant or Child Death | Death of infant or child before the 24 month study exam | Birth to 24 month study exam | 
| Number of Children With Sensorineural Hearing Loss | Sensorineural hearing loss is defined as the occurrence or non-occurrence of sensorineural hearing loss defined as unilateral and bilateral sensorineural hearing loss | 12 and 24 months corrected age | 
| Number of Children Diagnosed With Chorioretinitis | Chorioretinitis is defined as the occurrence or non-occurrence of chorioretinitis defined by ophthalmologic exam | 2 years of age | 
| Mean Cognitive Composite Scores From the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III) | 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. | 12 and 24 months corrected age | 
| Mean Motor Composite Scores From the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III) | 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. | 12 and 24 months corrected age | 
| Number of Infants or Children With the Composite Outcome | 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 | 24 month study exam | 
| Overall Child Status at 24 Months of Age | 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 | 24 month study exam | 
| Failure to Thrive at 24 Months | Failure to thrive defined as <10th percentile for weight at 24 months | 24 months of age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Perinatology, Cytomegalovirus immune globulin, Cytogam, CMVIG infusions