Asymptomatic Congenital CMV Treatment

This is a phase II, open-label trial to evaluate valganciclovir as a treatment to prevent development of sensorineural hearing loss (SNHL) in infants with asymptomatic congenital cytomegalovirus (CMV) infection. The trial will be conducted in two phases - screening of newborns to identify eligible subjects, and treatment of those newborns who have confirmed CMV infection at birth but without outward manifestations of congenital CMV infection. 229 newborns with confirmed CMV infection but without baseline SNHL and who meet all inclusion/exclusion criteria will be enrolled into the treatment phase. Study duration is 5 years. Primary objective of this study is to estimate the proportion of subjects with asymptomatic congenital CMV infection who, following treatment with 4 months of oral valganciclovir, develop SNHL by 6 months of life.

This is a phase II, open-label trial to evaluate valganciclovir as a treatment to prevent development of sensorineural hearing loss (SNHL) in infants with asymptomatic congenital cytomegalovirus (CMV) infection. The trial will be conducted in two phases - screening of newborns to identify eligible subjects, and treatment of those newborns who have confirmed CMV infection at birth but without outward manifestations of congenital CMV infection. Approximately 48,250 newborn infants with no outward manifestations of congenital CMV infection will be screened to detect approximately 241 neonates with asymptomatic congenital CMV infection; these 241 newborns then will have audiology examinations to determine baseline hearing, with approximately 229 having normal hearing in both ears. Those 229 newborns with confirmed CMV infection but without baseline SNHL and who meet all inclusion/exclusion criteria will be enrolled into the treatment phase. Enrolled subjects will be treated for four months with oral valganciclovir (16 mg/kg/dose, administered two times per day). Audiologic assessments will be made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. Treated infants will be followed for safety throughout the first 6 months of the study (including for 2 months post-treatment). Study duration is 5 years. Primary objective of this study is to estimate the proportion of subjects with asymptomatic congenital CMV infection who, following treatment with 4 months of oral valganciclovir, develop sensorineural hearing loss (SNHL) by 6 months of life. Secondary objectives are to: 1) define the safety and tolerability of valganciclovir in enrolled subjects, 2) estimate the proportion of subjects with asymptomatic congenital CMV infection who, following treatment with 4 months of oral valganciclovir, develop SNHL over the first 18 months of life.

Eligibility Criteria:
Inclusion Criteria:

* Parent(s)/legal guardian(s) have signed informed consent documents\*
* Confirmation of cytomegalovirus (CMV) by urine polymerase chain reaction (PCR) testing
* Infant \</= 30 days of age at initiation of study drug
* Weight at study enrollment \>/= 1775 grams
* Gestational age \>/= 32 weeks at birth

  * There is a screening informed consent for screening phase of study participation, and a treatment informed consent for treatment phase of study participation.

Exclusion Criteria:

* Symptomatic congenital cytomegalovirus (CMV) disease\*
* Sensorineural hearing deficits as detected by formal brainstem evoked response (not a screening auditory brainstem response (abr)) of known etiology other than CMV
* Prior or current receipt of ganciclovir, valganciclovir, foscarnet, cidofovir, brincidofovir, maribavir, or letermovir
* Maternal receipt of CMV hyperimmune globulin during pregnancy
* Breastfeeding from mother who is receiving ganciclovir, valganciclovir, foscarnet, cidofovir, brincidofovir, maribavir, or letermovir
* Gastrointestinal abnormality which might preclude absorption of an oral medication (e.g., a history of necrotizing enterocolitis)
* Infants known to be born to women who are HIV positive (HIV testing is not required for study entry)
* Current receipt of other investigational drugs

  * Symptomatic disease is defined as one or more of the following: 1) thrombocytopenia, if known; 2) petechiae; 3) hepatomegaly; 4) splenomegaly; 5) intrauterine growth restriction; 6) hepatitis (elevated transaminases and/or direct bilirubin), if known; 7) central nervous system involvement of the CMV disease (such as microcephaly; radiographic abnormalities indicative of CMV CNS disease, if known; abnormal CSF indices for age, if known; chorioretinitis, if known; and/or positive CMV PCR from CSF, if known).