Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a Randomized Controlled Trial (CONCERT)

1 Indication for further investigations (brain ultrasound). 2 Change of study design to efficacy study with historical control group.

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.

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 randomized before the age of 13 weeks to a treatment group (6 weeks valganciclovir 32 mg/kg daily dose; oral solution) or 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 25 infants in each treatment arm have been randomized. At 1 year follow-up hearing and child development are assessed. Hearing will be assessed with Brainstem Evoked Response Audiometry at an audiological center. Child development will be assessed during a home visit with the Bayley Scales of Infant Development III and parents will fill in the Dutch Child Development Inventory (NCDI) which will give more detailed information on communicative development of their child. 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 RCT 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.

Cytomegalovirus, Congenital infection, Sensorineural hearing loss, Randomized controlled trial, Valganciclovir

Infants in the control group receive no antiviral therapy. Counseling and treatment assigned by an audiological center remains unchanged.

Infants will be treated with valganciclovir for 6 weeks, 32 mg/kg daily dose in two doses, oral solution.

At 1 year follow-up hearing will be assessed with Brainstem Evoked Response Audiometry at an audiological center.

At 1 year follow-up child development will be assessed during a home visit with the Bayley Scales of Infant Development III. Additionally, parents will fill in the Dutch Child Development Inventory.

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 1 year).

Inclusion Criteria: 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. ≥ 37 weeks gestational age. Birth weight ≥ 2500 gram. Parental signed informed consent. Exclusion Criteria: Indications for symptomatic congenital CMV infection based on diagnostics carried out prior to the inclusion of the child in the trial. In case during the house visit the presence of a symptomatic CMV infection is doubted, inclusion will be discussed. Depending on the medical history taking, physical examination and laboratory tests inclusion will be decided upon. Treatment with other antiviral agents or immunoglobulins. Leucopenia < 0,5 x 10*9/L (blood sample tested at t=0).

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