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

A Phase III, Randomized, Placebo-Controlled Blinded Investigation of Six Weeks vs. Six Months of Oral Valganciclovir Therapy in Infants With Symptomatic Congenital Cytomegalovirus Infection (CASG 112)

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00466817

Enrollment

109

Registered

2007-04-27

Start date

2008-06-30

Completion date

2013-06-30

Last updated

2015-08-26

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cytomegalovirus Infection

Keywords

Cytomegalovirus, congenital, infants

Brief summary

Cytomegalovirus (CMV) infection is known to cause hearing loss and mental retardation. The purpose of this study is to compare a 6-week course to a 6-month course of the drug valganciclovir in babies born with CMV to assess the safety and efficacy of this treatment. Participants will include 104 infants (30 days old or younger) born with CMV disease. All infants will take valganciclovir by mouth for 6 weeks. At the end of the 6 week period, subjects will be assigned by chance to receive either valganciclovir or placebo (inactive substance) to complete the 6 months of antiviral treatment. Patients will be followed for the study related evaluations of safety, changes to hearing, and developmental milestones for up to 2 years. Patients will be followed by telephone contact for an additional 3 years. Thus, participants may be involved in study related procedures for approximately 5 years.

Detailed description

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.

Interventions

OTHERPlacebo

9 grams of powder which contains no Valganciclovir free base. The oral solution formulation comprises the following excipients: mannitol, lactose anhydrous, fumaric acid, sodium benzoate, saccharin sodium, flavor, and purified water.

DRUGValganciclovir

Mono-valyl ester pro-drug of ganciclovir, oral solution, provided as a 12 grams of powder containing 5 grams of Valganciclovir free base. The oral solution formulation comprises the following excipients: Providone K30, fumaric acid, sodium benzoate, sodium saccharin, mannitol, flavor, and purified water.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

No minimum to 30 Days

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Change in Best Ear Hearing Assessments at 6 Months.	Between baseline and 6 months	Hearing assessment was evaluated by an independent audiologist. At baseline, a brainstem evoked response (BSER) assessment and autoacoustic emissions (OAEs) hearing assessments were obtained. At 6 months, BSER and /or Visual reinforcement audiometry (VRA) and OAEs were obtained. A single, independent study audiologist who was blinded to treatment assignment assessed the audiology test battery for each subject and assigned the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications were assigned by ear (one for the left ear and one for the right ear), giving total ear classifications. Following this, the study audiologist assigned the best ear classification for the subject at that study visit; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the best ear classification was mild hearing loss.

Secondary

Measure	Time frame	Description
Adverse Events Which Lead to Permanent Discontinuation of Valganciclovir Therapy or Lead to Irreversible Outcome of the Adverse Event.	baseline through 7 months	Adverse events were assessed at each visit through month 7 of the study. No subject discontinued valganciclovir therapy due to permanent discontinuation of valganciclovir therapy or lead to irreversible outcome of any adverse event.
Change in Best Ear Hearing Assessments at 12 Months.	Between baseline and 12 months	Hearing assessment was evaluated by an independent audiologist. At baseline, a brainstem evoked response (BSER) assessment and autoacoustic emissions (OAEs) hearing assessments were obtained. At 12 months, BSER and /or Visual reinforcement audiometry (VRA) and OAEs were obtained. A single, independent study audiologist who was blinded to treatment assignment assessed the audiology test battery for each subject and assigned the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications were assigned by ear (one for the left ear and one for the right ear), giving total ear classifications. Following this, the study audiologist assigned the best ear classification for the subject at that study visit; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the best ear classification was mild hearing loss.
Change in Best Ear Hearing Assessments at 24 Months.	Between baseline and 24 months	Hearing assessment was evaluated by an independent audiologist. At baseline, a brainstem evoked response (BSER) assessment and autoacoustic emissions (OAEs) hearing assessments were obtained. At 24 months, BSER and /or Visual reinforcement audiometry (VRA) and OAEs were obtained. A single, independent study audiologist who was blinded to treatment assignment assessed the audiology test battery for each subject and assigned the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications were assigned by ear (one for the left ear and one for the right ear), giving total ear classifications. Following this, the study audiologist assigned the best ear classification for the subject at that study visit; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the best ear classification was mild hearing loss.
Number of Ears With Improvement or Protected Hearing in Hearing Assessments Over Left and Right Ears at 6 Months.(Based on 84 Ears From 43 Placebo Subjects and 82 Ears From 43 Valganciclovir Subjects)	Between baseline and 6 months	Hearing assessment was evaluated by an independent audiologist. At baseline, a brainstem evoked response (BSER) assessment and autoacoustic emissions (OAEs) hearing assessments were obtained. At 6 months, BSER and /or Visual reinforcement audiometry (VRA) and OAEs were obtained. A single, independent study audiologist who was blinded to treatment assignment assessed the audiology test battery for each subject and assigned the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications were assigned by ear (one for the left ear and one for the right ear), giving total ear classifications. Following this, the study audiologist assigned the best ear classification for the subject at that study visit; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the best ear classification was mild hearing loss.
Number of Ears With Improvement or Protected Hearing in Hearing Assessments Over Left and Right Ears at 12 Months.(Based on 77 Ears From 40 Placebo Subjects and 79 Ears From 41 Valganciclovir Subjects)	Between baseline and 12 months	Hearing assessment was evaluated by an independent audiologist. At baseline, a brainstem evoked response (BSER) assessment and autoacoustic emissions (OAEs) hearing assessments were obtained. At 12 months, BSER and /or Visual reinforcement audiometry (VRA) and OAEs were obtained. A single, independent study audiologist who was blinded to treatment assignment assessed the audiology test battery for each subject and assigned the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications were assigned by ear (one for the left ear and one for the right ear), giving total ear classifications. Following this, the study audiologist assigned the best ear classification for the subject at that study visit; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the best ear classification was mild hearing loss.
Number of Ears With Improvement or Protected Hearing Assessments Over Left and Right Ears at 24 Months.(Based on 58 Ears From 31 Placebo Subjects and 70 Ears From 37 Valganciclovir Subjects)	Between baseline and 24 months	Hearing assessment was evaluated by an independent audiologist. At baseline, a brainstem evoked response (BSER) assessment and autoacoustic emissions (OAEs) hearing assessments were obtained. At 24 months, BSER and /or Visual reinforcement audiometry (VRA) and OAEs were obtained. A single, independent study audiologist who was blinded to treatment assignment assessed the audiology test battery for each subject and assigned the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications were assigned by ear (one for the left ear and one for the right ear), giving total ear classifications. Following this, the study audiologist assigned the best ear classification for the subject at that study visit; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the best ear classification was mild hearing loss.
Number of Ears With Hearing Deterioration Over Left and Right Ears at 6 Months.(Based on 84 Ears From 43 Placebo Subjects and 82 Ears From 43 Valganciclovir Subjects)	Between baseline and 6 months	Hearing assessment was evaluated by an independent audiologist. At baseline, a brainstem evoked response (BSER) assessment and autoacoustic emissions (OAEs) hearing assessments were obtained. At 6 months, BSER and /or Visual reinforcement audiometry (VRA) and OAEs were obtained. A single, independent study audiologist who was blinded to treatment assignment assessed the audiology test battery for each subject and assigned the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications were assigned by ear (one for the left ear and one for the right ear), giving total ear classifications. Following this, the study audiologist assigned the best ear classification for the subject at that study visit; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the best ear classification was mild hearing loss.
Number of Ears With Hearing Deterioration Over Left and Right Ears at 12 Months.(Based on 77 Ears From 40 Placebo Subjects and 79 Ears From 41 Valganciclovir Subjects)	Between baseline and 12 months	Hearing assessment was evaluated by an independent audiologist. At baseline, a brainstem evoked response (BSER) assessment and autoacoustic emissions (OAEs) hearing assessments were obtained. At 12 months, BSER and /or Visual reinforcement audiometry (VRA) and OAEs were obtained. A single, independent study audiologist who was blinded to treatment assignment assessed the audiology test battery for each subject and assigned the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications were assigned by ear (one for the left ear and one for the right ear), giving total ear classifications. Following this, the study audiologist assigned the best ear classification for the subject at that study visit; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the best ear classification was mild hearing loss.
Number of Ears With Hearing Deterioration Over Left and Right Ears at 24 Months.(Based on 58 Ears From 31 Placebo Subjects and 70 Ears From 37 Valganciclovir Subjects)	Between baseline and 24 months	Hearing assessment was evaluated by an independent audiologist. At baseline, a brainstem evoked response (BSER) assessment and autoacoustic emissions (OAEs) hearing assessments were obtained. At 24 months, BSER and /or Visual reinforcement audiometry (VRA) and OAEs were obtained. A single, independent study audiologist who was blinded to treatment assignment assessed the audiology test battery for each subject and assigned the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications were assigned by ear (one for the left ear and one for the right ear), giving total ear classifications. Following this, the study audiologist assigned the best ear classification for the subject at that study visit; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the best ear classification was mild hearing loss.
Neurological Impairment at 12 Months of Life Utilizing the Bayley Scales of Infant and Toddler Development (Cognitive Composite Score).	12 Months after enrollment	Cognitive Composite Score for infants and toddlers was measured by use of the Bayley Scales of Infant and Toddler Development. For the Bayleys scoring of the Composite Scores, the range of scores is between 40 (very poor cognitive skills) and 160 (excellent cognitive skills), with the average cogonitive skills score for a child (age adjusted) is 100 with standard deviation of 15.
Neurological Impairment at 12 Months of Age Utilizing the Bayley Scales of Infant and Toddler Development (Receptive Communication Scaled Score).	12 Months after enrollment	Receptive Communication Scaled Score for infants and toddlers was measured by use of the Bayley Scales of Infant and Toddler Development. For the Bayleys scoring of the Scaled Scores, the range of scores is between 1 (very poor receptive communication skills) and 19 (excellent receptive communication skills), with the average receptive communication skills score for a child (age adjusted) is 10 with standard deviation of 3.
Neurological Impairment at 12 Months of Age Utilizing the Bayley Scales of Infant and Toddler Development (Expressive Communication Scaled Score).	12 Months after enrollment	Expressive Communication Scaled Score for infants and toddlers was measured by use of the Bayley Scales of Infant and Toddler Development. For the Bayleys scoring of the Scaled Scores, the range of scores is between 1 (very poor expressive communication skills) and 19 (excellent expressive communication skills), with the average expressive communication skills score for a child (age adjusted) is 10 with standard deviation of 3.
Neurological Impairment at 12 Months of Life Utilizing the Bayley Scales of Infant and Toddler Development (Language Composite Score).	12 Months after enrollment	Language Composite Score for infants and toddlers was measured by use of the Bayley Scales of Infant and Toddler Development. For the Bayleys scoring of the Composite Scores, the range of scores is between 40 (very poor language skills) and 160 (excellent language skills), with the average language skills score for a child (age adjusted) is 100 with standard deviation of 15.
Neurological Impairment at 12 Months of Life Utilizing the Bayley Scales of Infant and Toddler Development (Fine Motor Scaled Score).	12 Months after enrollment	Fine Motor Scaled Score for infants and toddlers was measured by use of the Bayley Scales of Infant and Toddler Development. For the Bayleys scoring of the Scaled Scores, the range of scores is between 1 (very poor fine motor skills) and 19 (excellent fine motor skills), with the average fine motor skills score for a child (age adjusted) is 10 with standard deviation of 3.
Neurological Impairment at 12 Months of Life Utilizing the Bayley Scales of Infant and Toddler Development (Gross Motor Scaled Score).	12 Months after enrollment	Gross Motor Scaled Score for infants and toddlers was measured by use of the Bayley Scales of Infant and Toddler Development. For the Bayleys scoring of the Scaled Scores, the range of scores is between 1 (very poor gross motor skills) and 19 (excellent gross motor skills), with the average gross motor skills score for a child (age adjusted) is 10 with standard deviation of 3.
Neurological Impairment at 12 Months of Life Utilizing the Bayley Scales of Infant and Toddler Development (Motor Composite Score).	12 Months after enrollment	Motor Composite Score for infants and toddlers was measured by use of the Bayley Scales of Infant and Toddler Development. For the Bayleys scoring of the Composite Scores, the range of scores is between 40 (very poor motor skills) and 160 (excellent motor skills), with the average motor skills score for a child (age adjusted) is 100 with standard deviation of 15.
Neurological Impairment at 24 Months Utilizing the Bayley Scales of Infant and Toddler Development (Receptive Communication Scaled Score).	24 Months after enrollment	Receptive Communication Scaled score for infants and toddlers was measured by use of the Bayley Scales of Infant and Toddler Development. For the Bayleys scoring of the Scaled Scores, the range of scores is between 1 (very poor receptive communication skills) and 19 (excellent receptive communication skills), with the average receptive communication skills score for a child (age adjusted) is 10 with standard deviation of 3.
Neurological Impairment at 24 Months of Life Utilizing the Bayley Scales of Infant and Toddler Development (Cognitive Composite Score).	24 months after enrollment	Cognitive Composite Score for infants and toddlers was measured by use of the Bayley Scales of Infant and Toddler Development. For the Bayleys scoring of the Composite Scores, the range of scores are between 40 (very poor cognitive skills) and 160 (excellent cognitive skills), with the average cognitive skills score for a child (age adjusted) is 100 with standard deviation of 15.
Neurological Impairment at 24 Months of Life, Utilizing the Bayley Scales of Infant and Toddler Development (Expressive Communication Scaled Score).	24 Months after enrollment	Expressive Communication Scaled Score for infants and toddlers was measured by use of the Bayley Scales of Infant and Toddler Development. For the Bayleys scoring of the Scaled Scores, the range of scores is between 1 (very poor expressive communication skills) and 19 (excellent expressive communication skills), with the average expressive communication skills score for a child (age adjusted) is 10 with standard deviation of 3.
Neurologic Impairment at 24 Months of Life Utilizing the Bayley Scales of Infant and Toddler Development (Language Composite Score).	24 Months after enrollment	Language Composite Score for infants and toddlers was measured by use of the Bayley Scales of Infant and Toddler Development. For the Bayleys scoring of the Composite Scores, the range of scores is between 40 (very poor language skills) and 160 (excellent language skills), with the average language skills score for a child (age adjusted) is 100 with standard deviation of 15.
Neurological Impairment at 24 Months, Utilizing the Bayley Scales of Infant and Toddler Development (Fine Motor Scaled Score).	24 Months after enrollment	Fine motor scaled score for infants and toddlers was measured by use of the Bayley Scales of Infant and Toddler Development. For the Bayleys scoring of the Scaled Scores, the range of scores is between 1 (very poor fine motor skills) and 19 (excellent fine motor skills), with the average fine motor skills score for a child (age adjusted) is 10 with standard deviation of 3.
Neurological Impairment at 24 Months of Life, Utilizing the Bayley Scales of Infant and Toddler Development (Gross Motor Scaled Score).	24 Months after enrollment.	Gross motor scaled score for infants and toddlers was measured by use of the Bayley Scales of Infant and Toddler Development. For the Bayleys scoring is between 1 (very poor gross motor skills) and 19 (excellent gross motor skills), with the average gross motor skills score for a child (age adjusted) is 10 with standard deviation of 3.
Neurological Impairment at 24 Months of Life, Utilizing the Bayley Scales of Infant and Toddler Development (Motor Composite Score).	24 Months after enrollment	Motor composite score for infants and toddlers was measured by use of the Bayley Scales of Infant and Toddler Development. For the Bayleys scoring of the Composite Scores, the range of scores is between 40 (very poor motor skills) and 160 (excellent motor skills), with the average motor skills score for a child (age adjusted) is 100 with standard deviation of 15.

Countries

United Kingdom, United States

Participant flow

Pre-assignment details

All 109 subjects started on valganciclovir. At the end of 6 weeks, subjects were randomized to valganciclovir or placebo. of the 109 subject that started, 12 dropped out before randomization and 1 subject was randomized but never received any blinded study drug.

Participants by arm

Arm	Count
Placebo: 6 Wks of Valganciclovir Followed by 18 Wks of Placebo Six weeks of oral Valganciclovir followed by placebo (18 weeks) to complete the six month time period. Placebo : 9 grams of powder which contains no Valganciclovir free base. The oral solution formulation comprises the following excipients: mannitol, lactose anhydrous, fumaric acid, sodium benzoate, saccharin sodium, flavor, and purified water.	49
Valganciclovir: 24 Wks of Valganciclovir Six months (6 weeks open label, 18 weeks blinded) of oral Valganciclovir. Valganciclovir : Mono-valyl ester pro-drug of ganciclovir, oral solution, provided as a 12 grams of powder containing 5 grams of Valganciclovir free base. The oral solution formulation comprises the following excipients: Providone K30, fumaric acid, sodium benzoate, sodium saccharin, mannitol, flavor, and purified water.	47
Total	96

Baseline characteristics

Characteristic	Placebo: 6 Wks of Valganciclovir Followed by 18 Wks of Placebo	Total	Valganciclovir: 24 Wks of Valganciclovir
Age, Continuous	19 weeks	15 weeks	14 weeks
Region of Enrollment United States	49 participants	96 participants	47 participants
Sex: Female, Male Female	20 Participants	36 Participants	16 Participants
Sex: Female, Male Male	29 Participants	60 Participants	31 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	3 / 13	45 / 47	47 / 49
serious Total, serious adverse events	1 / 13	11 / 47	19 / 49

Outcome results

Primary

Change in Best Ear Hearing Assessments at 6 Months.

Hearing assessment was evaluated by an independent audiologist. At baseline, a brainstem evoked response (BSER) assessment and autoacoustic emissions (OAEs) hearing assessments were obtained. At 6 months, BSER and /or Visual reinforcement audiometry (VRA) and OAEs were obtained. A single, independent study audiologist who was blinded to treatment assignment assessed the audiology test battery for each subject and assigned the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications were assigned by ear (one for the left ear and one for the right ear), giving total ear classifications. Following this, the study audiologist assigned the best ear classification for the subject at that study visit; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the best ear classification was mild hearing loss.

Time frame: Between baseline and 6 months

Population: Only subjects randomized and subjects that had both baseline and 6 month hearing exams were analyzed for the primary endpoint. Some subjects failed to have the one or both of the two hearing exams (baseline and/or 6 months). There were 43 subject in each group (placebo and active) that had both hearing results reported

Arm	Measure	Group	Value (NUMBER)
Placebo: 6 Wks Valganciclovir Followed by 18 Wks Placebo	Change in Best Ear Hearing Assessments at 6 Months.	Worsened	3 participants
Placebo: 6 Wks Valganciclovir Followed by 18 Wks Placebo	Change in Best Ear Hearing Assessments at 6 Months.	No Change	37 participants
Placebo: 6 Wks Valganciclovir Followed by 18 Wks Placebo	Change in Best Ear Hearing Assessments at 6 Months.	One point improvement	3 participants
Valganciclovir: 24 Wks of Valganciclovir	Change in Best Ear Hearing Assessments at 6 Months.	Worsened	5 participants
Valganciclovir: 24 Wks of Valganciclovir	Change in Best Ear Hearing Assessments at 6 Months.	No Change	36 participants
Valganciclovir: 24 Wks of Valganciclovir	Change in Best Ear Hearing Assessments at 6 Months.	One point improvement	2 participants

Secondary

Adverse Events Which Lead to Permanent Discontinuation of Valganciclovir Therapy or Lead to Irreversible Outcome of the Adverse Event.

Adverse events were assessed at each visit through month 7 of the study. No subject discontinued valganciclovir therapy due to permanent discontinuation of valganciclovir therapy or lead to irreversible outcome of any adverse event.

Time frame: baseline through 7 months

Arm	Measure	Group	Value (NUMBER)
Placebo: 6 Wks Valganciclovir Followed by 18 Wks Placebo	Adverse Events Which Lead to Permanent Discontinuation of Valganciclovir Therapy or Lead to Irreversible Outcome of the Adverse Event.	Permanent discontinuation of study drug	0 participants
Placebo: 6 Wks Valganciclovir Followed by 18 Wks Placebo	Adverse Events Which Lead to Permanent Discontinuation of Valganciclovir Therapy or Lead to Irreversible Outcome of the Adverse Event.	Irreversible outcome from use of study drug	0 participants
Valganciclovir: 24 Wks of Valganciclovir	Adverse Events Which Lead to Permanent Discontinuation of Valganciclovir Therapy or Lead to Irreversible Outcome of the Adverse Event.	Permanent discontinuation of study drug	0 participants
Valganciclovir: 24 Wks of Valganciclovir	Adverse Events Which Lead to Permanent Discontinuation of Valganciclovir Therapy or Lead to Irreversible Outcome of the Adverse Event.	Irreversible outcome from use of study drug	0 participants

Secondary

Change in Best Ear Hearing Assessments at 12 Months.

Hearing assessment was evaluated by an independent audiologist. At baseline, a brainstem evoked response (BSER) assessment and autoacoustic emissions (OAEs) hearing assessments were obtained. At 12 months, BSER and /or Visual reinforcement audiometry (VRA) and OAEs were obtained. A single, independent study audiologist who was blinded to treatment assignment assessed the audiology test battery for each subject and assigned the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications were assigned by ear (one for the left ear and one for the right ear), giving total ear classifications. Following this, the study audiologist assigned the best ear classification for the subject at that study visit; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the best ear classification was mild hearing loss.

Time frame: Between baseline and 12 months

Population: Only subjects randomized and subjects that had both baseline and 12 month hearing exams were analyzed for the primary endpoint. Some subjects failed to have the one or both of the two hearing exams (baseline and/or 12 months). There were 40 placebo subjects and 41 active drug subjects reported results for both time periods

Arm	Measure	Group	Value (NUMBER)
Placebo: 6 Wks Valganciclovir Followed by 18 Wks Placebo	Change in Best Ear Hearing Assessments at 12 Months.	Improved hearing	2 participants
Placebo: 6 Wks Valganciclovir Followed by 18 Wks Placebo	Change in Best Ear Hearing Assessments at 12 Months.	No change - normal hearing	23 participants
Placebo: 6 Wks Valganciclovir Followed by 18 Wks Placebo	Change in Best Ear Hearing Assessments at 12 Months.	No change - same degree of hearing loss	10 participants
Placebo: 6 Wks Valganciclovir Followed by 18 Wks Placebo	Change in Best Ear Hearing Assessments at 12 Months.	Worsening hearing	5 participants
Valganciclovir: 24 Wks of Valganciclovir	Change in Best Ear Hearing Assessments at 12 Months.	Worsening hearing	3 participants
Valganciclovir: 24 Wks of Valganciclovir	Change in Best Ear Hearing Assessments at 12 Months.	Improved hearing	2 participants
Valganciclovir: 24 Wks of Valganciclovir	Change in Best Ear Hearing Assessments at 12 Months.	No change - same degree of hearing loss	6 participants
Valganciclovir: 24 Wks of Valganciclovir	Change in Best Ear Hearing Assessments at 12 Months.	No change - normal hearing	30 participants

Secondary

Change in Best Ear Hearing Assessments at 24 Months.

Hearing assessment was evaluated by an independent audiologist. At baseline, a brainstem evoked response (BSER) assessment and autoacoustic emissions (OAEs) hearing assessments were obtained. At 24 months, BSER and /or Visual reinforcement audiometry (VRA) and OAEs were obtained. A single, independent study audiologist who was blinded to treatment assignment assessed the audiology test battery for each subject and assigned the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications were assigned by ear (one for the left ear and one for the right ear), giving total ear classifications. Following this, the study audiologist assigned the best ear classification for the subject at that study visit; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the best ear classification was mild hearing loss.

Time frame: Between baseline and 24 months

Population: Only subjects randomized and subjects that had both baseline and 24 month hearing exams were analyzed for the primary endpoint. Some subjects failed to have the one or both of the two hearing exams (baseline and/or 24 months). There were 31 placebo subjects and 37 active drug subjects reported results for both time periods

Arm	Measure	Group	Value (NUMBER)
Placebo: 6 Wks Valganciclovir Followed by 18 Wks Placebo	Change in Best Ear Hearing Assessments at 24 Months.	Improved hearing	2 participants
Placebo: 6 Wks Valganciclovir Followed by 18 Wks Placebo	Change in Best Ear Hearing Assessments at 24 Months.	No change - normal hearing	20 participants
Placebo: 6 Wks Valganciclovir Followed by 18 Wks Placebo	Change in Best Ear Hearing Assessments at 24 Months.	No change - same degree of hearing loss	7 participants
Placebo: 6 Wks Valganciclovir Followed by 18 Wks Placebo	Change in Best Ear Hearing Assessments at 24 Months.	Worsening hearing	2 participants
Valganciclovir: 24 Wks of Valganciclovir	Change in Best Ear Hearing Assessments at 24 Months.	Worsening hearing	3 participants
Valganciclovir: 24 Wks of Valganciclovir	Change in Best Ear Hearing Assessments at 24 Months.	Improved hearing	2 participants
Valganciclovir: 24 Wks of Valganciclovir	Change in Best Ear Hearing Assessments at 24 Months.	No change - same degree of hearing loss	2 participants
Valganciclovir: 24 Wks of Valganciclovir	Change in Best Ear Hearing Assessments at 24 Months.	No change - normal hearing	30 participants

Secondary

Neurological Impairment at 12 Months of Age Utilizing the Bayley Scales of Infant and Toddler Development (Expressive Communication Scaled Score).

Expressive Communication Scaled Score for infants and toddlers was measured by use of the Bayley Scales of Infant and Toddler Development. For the Bayleys scoring of the Scaled Scores, the range of scores is between 1 (very poor expressive communication skills) and 19 (excellent expressive communication skills), with the average expressive communication skills score for a child (age adjusted) is 10 with standard deviation of 3.