Congenital Cytomegalovirus: Efficacy of Antiviral Treatment

Study Overview
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Brief Summary
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The objective of the trial is to investigate whether early treatment with oral valganciclovir of infants with both congenital cytomegalovirus infection and sensorineural hearing loss can prevent progression of hearing loss.

Detailed Description
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In the Netherlands all neonates are routinely screened for hearing during the first weeks after birth with the Otoacoustic Emissions (OAE) procedure. After the second refer an Automated Auditory Brainstem Response (AABR) is performed. The parents of all newborns, born at ≥ 37 weeks gestational age, that fail this AABR in the Netherlands (about 550 yearly) will be asked for consent for CMV-testing on the dried blood spots. Newborns diagnosed with congenital CMV and with confirmed SNHL (≥ 20 dB) are eligible for inclusion. After informed consent infants will be offered treatment before the age of 13 weeks (6 weeks valganciclovir 32 mg/kg daily dose; oral solution). Parents may decide to participate in the trial in the control group (no antiviral treatment). Infants will be monitored for leucopenia and liver- and kidney function. Inclusion will continue for at least 1.5 years, or until at least 40 infants have been included in the trial. At age 20 months hearing and child development are assessed in the follow-up. Hearing will be assessed with Brainstem Evoked Response Audiometry with the Vivosonic Integrity. Child development will be assessed with the Bayley Scales of Infant Development III (official Dutch translation) and parents will fill in the Dutch Child Development Inventory (NCDI) which will give more detailed information on communicative development of their child. The hearing assessment and developmental examination will be fulfilled during a home visit. Viral loads in blood and urine will be monitored during antiviral treatment as well as twice in the control group. This study will provide information on the percentage of infants with a congenital CMV infection who fail the neonatal hearing screening . The trial will show whether early treatment of congenital CMV infected children with hearing impairment prevents deterioration of hearing loss and to what extent. The outcome may lead to implementation of congenital CMV testing in the neonatal hearing screening program or possibly into the newborn blood screening.

Official Title
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The Leiden CONCERT Study 2.0 Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a Non-Randomized Trial With Historical Control Group

Conditions
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Congenital Cytomegalovirus Infection, Sensorineural Hearing Loss

Intervention / Treatment
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* Drug: Valganciclovir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Treatment group and refusal control group Infants with congenital CMV infection, and hearing loss (≥ 20 dB, in one or both ears). Age at time of inclusion is ≤ 12 weeks after birth. Born at ≥ 37 weeks gestational age. Birth weight > -2 SD corrected for duration of pregnancy and ethnic origin. Parental signed informed consent. Historical control group Infants with congenital CMV infection, and hearing loss (≥ 20 dB, in one or both ears). Age at time of inclusion is > 13 weeks after birth. Born at ≥ 37 weeks gestational age. Birth weight > -2 SD corrected for duration of pregnancy and ethnic origin. Parental signed informed consent. Exclusion Criteria Treatment group and refusal control group Previously noted (≤ 12 weeks after birth) symptoms possibly related to congenital CMV, for which medical attention was requested. For example: intra uterine growth retardation, petechiae, hepatosplenomegaly, jaundice, microcephaly, thrombocytopenia, elevated transaminases, elevated bilirubin. Treatment with other antiviral agents or immunoglobulins. Solely applicable for treatment group: leucopenia < 0,5 x 10*9/L (blood sample tested at t=0). Historical control group Previously encountered (≤ 12 weeks after birth) symptoms possibly related to congenital CMV, for which medical attention was requested For example: intra uterine growth retardation, petechiae, hepatosplenomegaly, jaundice, microcephaly, thrombocytopenia, elevated transaminases, elevated bilirubin. Treatment with (val)ganciclovir. Treatment with other antiviral agents or immunoglobulins.

Ages Eligible for Study
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Minimum Age: 3 Weeks
Maximum Age: 12 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Valganciclovir<br>Valganciclovir 32 mg/kg per day in two doses (16 mg/kg per dose) during 6 weeks in an oral solution. | Drug: Valganciclovir<br>* Infants will be treated with valganciclovir for 6 weeks, 32 mg/kg daily dose in two doses, oral solution.<br>* Other names: Valganciclovirhydrochloride;|
| No Intervention: Control<br>Refusal control group: Infants in the control group receive no antiviral therapy. Counseling and treatment assigned by an audiological center remain unchanged. Historical control group: Infants with birth date 1-11-2011 till 1-07-2012 with sensorineural hearing loss and congenital CMV. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hearing assessment | At 20 months of age hearing will be assessed with Brainstem Evoked Response Audiometry using the Vivosonic Integrity during a home visit. | Age: 20 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Child development | At age 20 months child development will be assessed during a home visit with the Bayley Scales of Infant Development III (official Dutch translation). Additionally, parents will fill in the Dutch Child Development Inventory. | Age: 20 months | 
| Viral load | Viral blood load will be monitored in the treatment group(at baseline, weekly during antiviral treatment, and one week after treatment) as well as in the control group (baseline and 7 weeks after inclusion). Viral urine load will be monitored in the treatment group and in the control group (at baseline, weekly during 7 weeks after inclusion, and at the age of 20 months). | Baseline, weekly during 7 weeks, and at 20 months of age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cytomegalovirus, Congenital infection, Sensorineural hearing loss, Valganciclovir