Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants

Cytomegalovirus (CMV) can be transmitted from the mother to the fetus and is a leading cause
of sensorineural hearing loss (SNHL), which is a condition where the inner ear is unable to
convert sound into nerve impulses to the brain. This hearing loss and its detrimental effect
on language development contribute nearly $4 billion annually to the health care costs in the
U.S. Unlike other types of SNHL, CMV induced hearing loss can be treated. Several clinical
trials have demonstrated that antiviral therapy may prevent progressive hearing loss if
administered early in life for severely affected (symptomatic CMV) infants. These promising
findings have given rise to a debate regarding the best method for identifying and treating
the more numerous asymptomatic CMV-infected infants.

One approach is to conduct universal newborn hearing screens, and then do CMV diagnostic
testing only on the infants who fail the hearing screen. This targeted approach should
identify those infants at greatest risk of developing progressive hearing loss and consequent
communicative difficulties. Utah is the first state to mandate this approach whereby infants
under three weeks of age who fail their newborn hearing screening undergo CMV testing. In
this trial, the hearing screen targeted approach will be used to identify patients eligible
for participation in a double blind placebo controlled randomized clinical trial of antiviral
valganciclovir therapy. The results of this trial will inform public policy, potentially
shift our current clinical practice regarding pediatric hearing loss evaluation, and
potentially offer a therapeutic option to asymptomatic CMV-infected infants with SNHL.

Inclusion Criteria:

- Age greater than or equal to 1 month and less than or equal to 6 months at the time of
randomization; AND

- Greater than or equal to 37 weeks gestational age at birth; AND

- Positive congenital CMV by urine culture or polymerase chain reaction test(PCR), OR
saliva culture or PCR followed by confirmatory urine PCR by 21 days of age, OR urine
culture or PCR after 21 days of age followed by newborn dry blood spot PCR; AND

- Confirmed sensorineural hearing loss (SNHL) by auditory brainstem response (ABR)
testing. For ABR assessments, hearing loss is defined as levels greater than 25 dB
normal hearing levels (NHL) at 1, 2, or 4 kHz in one or both ears.

Exclusion Criteria:

- Imminent demise; OR

- Known hypersensitivity reaction to valganciclovir, ganciclovir, or any components of
the investigational product formulation; OR

- ALT (Alanine Aminotransferase) five times baseline U/L, hepatomegaly, or significant
gastrointestinal disorders (e.g., eosinophilic esophagitis, ulcerative colitis); OR

- Absolute neutrophil count (ANC) less than 500 cells/mm^3, Hemoglobin less than 8 g/dL,
or platelets less than 50,000/mm^3, splenomegaly, or significant hematologic disorders
(e.g., hemophilia, leukemia, sickle cell anemia); OR

- Creatinine clearance less than 60 mL/min/1.73m^2 or significant renal disorders (e.g.,
nephrotic syndrome); OR

- Potassium greater than 5.5 mEq/L; OR

- Receiving other antiviral medications or immune globulin therapy; OR

- Receiving other investigational drugs; OR

- Breast feeding from a mother receiving antiviral or immunosuppressive medication; OR

- Known HIV positive mother (risk of immunosuppression); OR

- Subject is currently using list of prohibited medication specified by the package
insert; OR

- Other known cause contributing to SNHL (e.g., meningitis, aminoglycoside ototoxicity);
OR

- Bilateral profound SNHL or auditory neuropathy spectrum disorder; OR

- Existing conductive hearing loss or mixed permanent hearing loss is present; OR

- Evidence of intracranial calcification; OR

- Evidence of hydrocephalus; OR

- Microcephaly; OR

- Presence of petechiae; OR

- Intrauterine growth retardation; OR

- Chorioretinitis, optic atrophy or pale optic nerves; OR

- Parent or guardian unable to speak English or Spanish; OR

- Subject exposed to a language other than English or Spanish a majority of the time; OR

- Subject unable to complete hearing assessments or parent/guardian unable to complete
communication questionnaires.