Investigation of Six Weeks of Oral Valganciclovir Therapy in Infants and Children With Congenital Cytomegalovirus Infection and Hearing Loss

• The proportion of children who have viruria detected by PCR [ Time Frame: 6 weeks and six months after trial entry ] [ Designated as safety issue: No ]
• The quantitative log reduction in viruria [ Time Frame: Baseline to end of 6 weeks of therapy ] [ Designated as safety issue: No ]
• The proportion of children who have viremia [ Time Frame: 6 weeks and six months after trial entry ] [ Designated as safety issue: No ]
• The quantitative log reduction in viremia [ Time Frame: Baseline to end of 6 weeks of therapy ] [ Designated as safety issue: No ]
• The proportion of children who have CMV detected in saliva by PCR [ Time Frame: 6 weeks and six months after trial entry ] [ Designated as safety issue: No ]
• The quantitative log reduction in CMV viral load in saliva [ Time Frame: Baseline to end of 6 weeks of therapy ] [ Designated as safety issue: No ]
• The proportion of children whose sensorineural hearing improves or remains unchanged from baseline when measured [ Time Frame: Baseline to 6 months ] [ Designated as safety issue: No ]

Valganciclovir is a mono-valyl ester pro-drug of ganciclovir, which is rapidly converted to ganciclovir on absorption. Valganciclovir is approved for the treatment of Cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS), and for the prevention of CMV disease in kidney, heart, and kidney-pancreas high-risk transplant patients. The formulation used in this study will be valganciclovir oral solution which is commercially available. It will be provided as a 12g powder containing 5g valganciclovir free base. The oral solution formulation comprises the following excipients: Providone K30, fumaric acid, sodium benzoate, sodium saccharin, mannitol, flavor, and purified water. The valganciclovir oral solution formulation does not contain lactose anhydrous.

The placebo comparator will be commercially available Simple Syrup as 85-90% sucrose.

Upon enrollment, study subjects will be randomized to six weeks of oral valganciclovir or six weeks of oral placebo. Study subjects will be stratified according to age (less than 24 months vs. greater than or equal to 24 months) at study entry. The target number of enrolled evaluable subjects will be 54. Dropouts and subjects with audiology assessments that are inadequate for study comparison will be replaced. During the six week treatment period and the 2 weeks thereafter, study subjects will be followed every 2 weeks. Between Study Day 56 and Study Month 6, study subjects will be followed every 8 weeks (Study Months 4 and 6).

At each of the visits during the treatment phase (Study Days 1, 14, 28, and 42), safety labs will be assessed; viral load specimens from blood, urine, and saliva will be obtained; adverse events will be assessed; and concurrent medications will be recorded. Ganciclovir concentrations for population pharmacokinetic assessment will be obtained at each study visit while the subject is receiving study medication. Dose adjustments for weight change will occur at study visits during the subject's treatment period, and may also occur at any time during the treatment period as indicated per protocol for neutropenia, thrombocytopenia, or renal impairment. At the Study Day 56 visit, safety labs will be obtained; viral load specimens from blood, urine, and saliva will be obtained; and adverse events will be assessed. Hearing will be assessed at baseline and at Study Month 6.

Changes in whole blood viral load measurements will be correlated with hearing outcomes. In study subjects with increasing whole blood viral loads during the course of treatment, antiviral resistance may be evaluated. A Data and Safety Monitoring Board (DSMB) will be established to oversee the accrual, performance, safety, and efficacy of the trial.

• Congenital Cytomegalovirus
• Hearing Loss

• Drug: Valganciclovir
  Valganciclovir will be administered at 16mg/kg body weight
• Drug: Placebo
  The placebo comparator will be commercially available Simple Syrup as 85-90% sucrose.

• Active Comparator: Valganciclovir
  Intervention: Drug: Valganciclovir
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

Inclusion Criteria:•Signed informed consent from parent(s) or legal guardian(s)

• Sensorineural hearing loss (≥ 21dB in one or both ears, documented within 8 weeks prior to study entry)
• Children from 1 month through 3 years of age (up to the 4th birthday)
• CMV shedding in urine by PCR or culture (including shell vial) within 8 weeks prior to study enrollment
• CMV detected within 30 days of birth (urine, blood, or saliva tested as neonate; or Guthrie card-positive)

Exclusion Criteria:•Imminent demise

• Profound sensorineural hearing loss (> 90dB) in both ears
• 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 < 10 mL/min/1.73m2 at time of study enrollment
• Breastfeeding from mother who is receiving ganciclovir, valganciclovir, foscarnet, cidofovir, or maribavir
• Infants known to be born to women who are HIV positive (but HIV testing is not required for study entry).
• Current receipt of other investigational drugs
• Previous receipt of ganciclovir or valganciclovir
• Inability to attend follow-up hearing and clinical assessments
• Infants with Auditory neuropathy/dyssynchrony.
• Children with another confirmed etiology for SNHL (e.g. connexin 26, syndrome or metabolic disorder associated with SNHL, inner ear malformation and widened vestibular aqueducts, meningitis). Full exclusion of these conditions is not essential for trial enrollment.