Valganciclovir Therapy in Infants and Children With Congenital CMV Infection and Hearing Loss

Congenital cytomegalovirus (CMV) infection is the most frequent known viral cause of mental
retardation, and is the leading non-genetic cause of sensorineural hearing loss in many
countries including the United States. This is a Phase II international, multi-center,
double-blind, placebo-controlled evaluation of 6 weeks of oral valganciclovir treatment or 6
weeks of placebo for fifty-four male and female infants/toddlers 1 month through 3 years of
age (up to 4 years of age) with virologically-confirmed congenital CMV infection and hearing
loss. Patient who are between 1 month and 4 years of age and who have SNHL (Sensorineural
Hearing Loss) and are eligible for enrollment. The expected study duration is 3.5 years from
enrollment of first study subject. The primary objective is to assess whether a six week
course of oral valganciclovir can stabilize the hearing of children with congenital CMV
infection who present with hearing loss. The secondary objective is to define the following
responses as a function of systemic exposure to ganciclovir (active metabolite of
valganciclovir): CMV viral load in blood; CMV viral load in urine; and CMV viral load in
saliva. Also, to define the safety and tolerability of valganciclovir in enrolled subjects.
The tertiary objective is to define the pharmacokinetics of ganciclovir (metabolite)
following administration of valganciclovir (prodrug) in enrolled subjects.

Inclusion Criteria:

1. Signed informed consent from parent(s) or legal guardian(s)

2. Sensorineural hearing loss (>/= 21dB in one or both ears, documented within 12 weeks
prior to study entry)

3. Children from 1 month through 3 years of age (up to the 4th birthday)

Exclusion Criteria:

1. Imminent demise

2. Profound sensorineural hearing loss (> 90dB) in both ears

3. Patients receiving other antiviral agents or immune globulin

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

5. Documented renal insufficiency, as noted by a creatinine clearance < 10 mL/min/1.73m2
at time of study enrollment

6. Breastfeeding from mother who is receiving ganciclovir, valganciclovir, foscarnet,
cidofovir, or maribavir

7. Infants known to be born to women who are HIV positive (but HIV testing is not
required for study entry).

8. Current receipt of other investigational drugs

9. Previous receipt of ganciclovir or valganciclovir

10. Known hypersensitivity to ganciclovir, valganciclovir, or components of the product

11. Inability to attend follow-up hearing and clinical assessments

12. Infants with Auditory neuropathy/dyssynchrony.

13. Children with another known etiology for SNHL (e.g. connexin 26, syndrome or metabolic
disorder associated with SNHL, inner ear malformation and widened vestibular
aqueducts, meningitis).

Exclusion of each of these conditions is not required for trial enrollment.