Short-Term vs. Long-Term Valganciclovir Therapy for Symptomatic Congenital CMV Infections

This study is a multi-center, prospective, international, Phase III, randomized and blinded
investigation of 6 weeks versus 6 months of oral valganciclovir therapy in babies with
symptomatic congenital cytomegalovirus (CMV) disease. Following enrollment, study subjects
will receive 6 weeks of oral valganciclovir. Near the end of the 6-week course, subjects will
be randomized in a 1:1 fashion either to continue on valganciclovir to complete 6 months of
therapy or to begin a matching placebo to complete the 6 months. Study subjects will be
stratified according to whether or not there is central nervous system (CNS) involvement at
study entry. During the 6-month treatment period and the 1 month thereafter, study subjects
will be followed weekly for 4 weeks, then every other week for 8 weeks, then every month for
4 months. At each of these visits, safety labs will be checked, growth parameters recorded,
and adverse events assessed. The dose of study medication will be adjusted for weight gain at
each of these study visits. Dose adjustments may also occur as indicated per protocol for
neutropenia, thrombocytopenia, or renal impairment. Whole blood will be obtained for CMV
viral load at each of these visits as well. Hearing outcomes will be assessed at baseline, 6
months, 12 months and 24 months. Developmental outcomes will be assessed at 12 months and 24
months. Changes in whole blood viral load measurements will be correlated with both hearing
and neurologic outcomes. In study subjects with increasing whole blood viral loads during the
course of treatment, assessment for antiviral resistance may be undertaken.Safety assessments
include: hematology labs, chemistry labs, physical examinations, and adverse event data
performed/collected serially. Development of neutropenia will be confirmed by repeat blood
testing within one week, and study drug will be held until it resolves. Efficacy assessments
include: hearing assessments at baseline, 6 months, 12 months and 24 months; and
neurodevelopmental assessments at 12 months and 24 months. Study objectives are: to compare
the impact on hearing outcomes of 6 weeks versus 6 months of antiviral treatment with
valganciclovir oral solution in infants with symptomatic congenital CMV disease; to compare
the safety profile of 6 weeks versus 6 months of antiviral therapy with valganciclovir oral
solution in infants with symptomatic congenital CMV disease; to compare the impact on
neurologic outcomes of 6 weeks versus 6 months of antiviral treatment with valganciclovir
oral solution in infants with symptomatic congenital CMV disease; and to correlate change in
whole blood viral load with hearing and neurologic outcomes. Participants will include 104
male and female neonates (less than or equal to 30 days) with symptomatic congenital CMV.

Inclusion Criteria:

- Signed informed consent from parent(s) or legal guardian(s)

- Confirmation of cytomegalovirus (CMV) from urine or throat swab specimens by culture,
shell vial, or polymerase chain reaction (PCR) tests

- Symptomatic congenital CMV disease, as manifest by one or more of the following:

1. Thrombocytopenia

2. Petechiae

3. Hepatomegaly

4. Splenomegaly

5. Intrauterine growth restriction

6. Hepatitis (elevated transaminases and/or bilirubin)

7. Central nervous system (CNS) involvement of the CMV disease [such as
microcephaly, radiographic abnormalities indicative of CMV CNS disease, abnormal
cerebrospinal fluid (CSF) indices for age, chorioretinitis, hearing deficits as
detected by formal brainstem evoked response (not a screening auditory brainstem
response {ABR}), and/or positive CMV PCR from CSF]

- Less than or equal to 30 days of age at study enrollment

- Weight at study enrollment greater than or equal to 1800 grams

- Gestational age greater than or equal to 32 weeks at birth

Exclusion Criteria:

- Imminent demise

- Patients receiving other antiviral agents or immune globulin

- Gastrointestinal abnormality which might preclude absorption of an oral medication
(e.g., a history of necrotizing enterocolitis)

- Documented renal insufficiency, as noted by a creatinine clearance less than 10
mL/min/1.73m^2 at time of study enrollment

- Breastfeeding from mother who is receiving ganciclovir, valganciclovir, foscarnet,
cidofovir, or maribivir

- Infants known to be born to women who are human immunodeficiency virus (HIV) positive
(but HIV testing is not required for study entry)

- Current receipt of other investigational drugs