Clinical trial NCT01376778: A Randomized Trial to Prevent Congenital Cytomegalovirus (CMV)
Official title: A Randomized Trial to Prevent Congenital Cytomegalovirus (CMV)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Congenital Cytomegalovirus Infection
Maternal Cytomegalovirus Infection
Keywords: Perinatology
Cytomegalovirus immune globulin
Cytogam
CMVIG infusions
Lead sponsor: The George Washington University Biostatistics Center
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2011-06-20
Enrollment: 399
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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). 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.

Eligibility 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

Primary outcomes:
measure: Number of Participants With the Composite Primary Outcome
timeFrame: From randomization through 3 weeks of life
measure: Number of Participants Who Had a Fetus or Neonate With CMV Infection
timeFrame: From randomization through 3 weeks of life
measure: Number of Participants Who Had a Neonatal Death Without CMV Infection
timeFrame: From randomization through 3 weeks of life
measure: Number of Participants With a Fetal or Neonatal Death With Proven CMV Infection
timeFrame: From randomization through 3 weeks of life
measure: Number of Participants With Fetal Death Without Proven CMV Infection
timeFrame: From randomization through delivery
Secondary outcomes:
measure: Number of Participants With Gestational Hypertension or Preeclampsia
timeFrame: from randomization through discharge from the hospital
measure: Number of Participants With Placental Abruption
timeFrame: From randomization through delivery (maximum 42 weeks gestation)
measure: Median Gestational Age at Delivery
timeFrame: Delivery
measure: Number of Participants Whose Gestational Age at Delivery Was Before 37 Weeks
timeFrame: Delivery before 37 weeks gestation
measure: Number of Participants Whose Gestational Age at Delivery Was Before 34 Weeks, 0 Days
timeFrame: Delivery before 34 weeks gestation
measure: Number of Participants Reporting Yes or no to Medication Side Effects
timeFrame: From randomization (10-27 weeks gestation) through delivery (maximum 42 weeks gestation)
measure: Number of Participants Who Had a Fetal or Neonatal Death
timeFrame: From randomization (10-27 weeks gestation) through delivery (maximum 42 weeks gestation) up to 120 days of life
measure: Median Neonatal Head Circumference
timeFrame: 72 hours postpartum
measure: Median Birth Weight
timeFrame: Delivery
measure: Number of Participants With Fetal Growth Restriction
timeFrame: Delivery
measure: Number of Participants With Symptomatic CMV Infection
timeFrame: During pregnancy up to 3 weeks postpartum
measure: Number of Neonates With Grade 3 or 4 Intraventricular Hemorrhage
timeFrame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner
measure: Number of Neonates With Ventriculomegaly
timeFrame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner
measure: Number of Neonates With Retinopathy of Prematurity (ROP)
timeFrame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner
measure: Number of Neonates With Respiratory Distress Syndrome
timeFrame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner
measure: Number of Neonates With Chronic Lung Disease
timeFrame: 28 days of life
measure: Number of Neonates With Necrotizing Enterocolitis (NEC)
timeFrame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner
measure: Number of Neonates With Hyperbilirubinemia
timeFrame: From birth to 1 week of life
measure: Number of Neonates With Suspected Neonatal Sepsis
timeFrame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner
measure: Number of Neonates With Neonatal Pneumonia
timeFrame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner
measure: Number of Neonates Experiencing Seizures / Encephalopathy
timeFrame: 0 days to approximately 120 days of life or hospital discharge, whichever is sooner
measure: Median Length of Neonatal Hospital Stay
timeFrame: birth to neonatal hospital discharge (usually a maximum of 120 days)
measure: Number of Participants Experiencing Infant or Child Death
timeFrame: Birth to 24 month study exam
measure: Number of Children With Sensorineural Hearing Loss
timeFrame: 12 and 24 months corrected age
measure: Number of Children Diagnosed With Chorioretinitis
timeFrame: 2 years of age
measure: Mean Cognitive Composite Scores From the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III)
timeFrame: 12 and 24 months corrected age
measure: Mean Motor Composite Scores From the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III)
timeFrame: 12 and 24 months corrected age
measure: Number of Infants or Children With the Composite Outcome
timeFrame: 24 month study exam
measure: Overall Child Status at 24 Months of Age
timeFrame: 24 month study exam
measure: Failure to Thrive at 24 Months
timeFrame: 24 months of age
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama - Birmingham
state: Alabama
city: Stanford
country: United States
facility: Stanford University
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: New York
country: United States
facility: Columbia University
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina - Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cleveland
country: United States
facility: Case Western Reserve-Metrohealth
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Magee Womens Hospital of UPMC
state: Pennsylvania
city: Providence
country: United States
facility: Brown University
state: Rhode Island
city: Dallas
country: United States
facility: University of Texas - Southwestern Medical Center
state: Texas
city: Galveston
country: United States
facility: University of Texas - Galveston
state: Texas
city: Houston
country: United States
facility: University of Texas - Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Medical Center
state: Utah
Study officials:
affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Monica Longo, MD
role: STUDY_DIRECTOR
affiliation: George Washington University
name: Rebecca Clifton, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Brown University
name: Brenna Hughes, MD
role: STUDY_CHAIR
References:
citation: Hughes BL, Clifton RG, Rouse DJ, Saade GR, Dinsmoor MJ, Reddy UM, Pass R, Allard D, Mallett G, Fette LM, Gyamfi-Bannerman C, Varner MW, Goodnight WH, Tita ATN, Costantine MM, Swamy GK, Gibbs RS, Chien EK, Chauhan SP, El-Sayed YY, Casey BM, Parry S, Simhan HN, Napolitano PG, Macones GA; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. A Trial of Hyperimmune Globulin to Prevent Congenital Cytomegalovirus Infection. N Engl J Med. 2021 Jul 29;385(5):436-444. doi: 10.1056/NEJMoa1913569.
citation: Rouse DJ, Fette LM, Hughes BL, Saade GR, Dinsmoor MJ, Reddy UM, Pass R, Allard D, Mallett G, Clifton RG, Saccoccio FM, Permar SR, Gyamfi-Bannerman C, Varner MW, Goodnight WH, Tita ATN, Costantine MM, Swamy GK, Heyborne KD, Chien EK, Chauhan SP, El-Sayed YY, Casey BM, Parry S, Simhan HN, Napolitano PG, Macones GA; for the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. Noninvasive Prediction of Congenital Cytomegalovirus Infection After Maternal Primary Infection. Obstet Gynecol. 2022 Mar 1;139(3):400-406. doi: 10.1097/AOG.0000000000004691.
citation: Dinsmoor MJ, Fette LM, Hughes BL, Rouse DJ, Saade GR, Reddy UM, Allard D, Mallett G, Thom EA, Gyamfi-Bannerman C, Varner MW, Goodnight WH, Tita ATN, Costantine MM, Swamy GK, Heyborne KD, Chien EK, Chauhan SP, El-Sayed YY, Casey BM, Parry S, Simhan HN, Napolitano PG, Macones GA; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (MFMU) Network. Amniocentesis to diagnose congenital cytomegalovirus infection following maternal primary infection. Am J Obstet Gynecol MFM. 2022 Jul;4(4):100641. doi: 10.1016/j.ajogmf.2022.100641. Epub 2022 May 6.