Leiden CONCERT study 2.0
Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a non-Randomized Trial with Historical Control Group
The objective of the Leiden CONCERT study 2.0 is to investigate whether early valganciclovir treatment of children with hearing loss (≥ 20 dB unilateral or bilateral), and a confirmed congenital CMV infection can prevent deterioration of the hearing loss at 20 months. It is an efficacy trial across the Netherlands with valganciclovir (6 weeks) in newborns with congenital CMV and hearing loss diagnosed at an audiological center. At 20 months 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.
Antiviral treatment - background
Valganciclovir has known antiviral effect on CMV and is used extensively in the treatment of CMV infections in immunocompromised patients. For congenital CMV infections one randomized controlled trial has been performed that shows efficacy on hearing loss in infants with symptomatic congenital CMV (clinically apparent disease in the newborn period with possible symptoms: microcephaly, intracranial calcifications, chorioretinitis and/or hearing loss). Insufficient results exist on the effect of antiviral treatment in newborns with solely hearing loss and no clinically apparent disease in the newborn period. Due to the often progressive nature of the hearing loss with a congenital CMV infection, antiviral treatment could prevent the further progression of the hearing loss. It is probable that the treatment is more effective with an earlier start of the treatment.
All neonates are routinely screened in the Netherlands for hearing during the first weeks after birth with the Otoacoustic Emissions procedure. After the second refer an Automated Auditory Brainstem Response is performed. The parents of all newborns who fail this Automated Auditory Brainstem Response in the Netherlands (about 550 yearly) will be asked for consent for CMV-testing on the dried blood spots. Infants diagnosed with congenital CMV and with confirmed sensorineural hearing loss (≥ 20 dB unilateral of bilateral) are eligible for inclusion. After informed consent parents choose in which trial group their infant is included: the treatment or the control group. For inclusion infants are under the age of 13 weeks. A total of 40 – 50 infants will be included in the trial. According to the number of infants referred in the hearing screening program it is estimated that in 2016 enough infants will have been included in the CONCERT study 2.0.
Antiviral treatment in the trial
Infants in the treatment group receive valganciclovir for 6 weeks with a daily dose of 32 mg/kg in two doses. Valganciclovir is administered as an oral solution. Infants will be monitored for leucopenia and liver- and kidney function on a weekly basis. Untreated infants will have two blood samples checked for leucopenia and liver- and kidney function. Parents of infants in both the treatment and the control group will keep a diary for possible ‘adverse events’. Viral loads in blood and urine will be monitored during antiviral treatment as well as twice in the control group.
Historical control group
Parents of infants with hearing loss born between 1-11-2011 and 1-07-2012, have been approached for CMV diagnostics. Once congenital CMV has been diagnosed parents are asked to participate in the follow-up of the CONCERT study: hearing and developmental assessment at the age of around 20 months.
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 (no clinical apparent disease in the newborn period) 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.