Asymptomatic Congenital CMV Treatment

This is a phase II, open-label trial to evaluate valganciclovir as a treatment to prevent
development of SNHL in infants with asymptomatic congenital 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.

Substudy:

Through the screening process, approximately 12 neonates congenitally infected with CMV who
have SNHL at birth also will be identified. Newborn patients with SNHL and who are being
treated clinically with valganciclovir will be offered enrollment into an observational
substudy.

Inclusion Criteria:

- Parent(s)/legal guardian(s) have signed informed consent documents*

- Confirmation of CMV by saliva PCR testing

- Infant
- 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 CMV disease*

- Sensorineural hearing deficits as detected by formal brainstem evoked response (not a
screening 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).