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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Cytomegalovirus Infection

Intervention / Treatment
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* Other: Placebo
* Drug: Valganciclovir


Participation Criteria
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Eligibility Criteria
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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: Thrombocytopenia Petechiae Hepatomegaly Splenomegaly Intrauterine growth restriction Hepatitis (elevated transaminases and/or bilirubin) 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

Ages Eligible for Study
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Maximum Age: 30 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Valganciclovir<br>Six months of oral Valganciclovir. | Drug: Valganciclovir<br>* 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.<br>|
| Placebo Comparator: Placebo<br>Six weeks of oral Valganciclovir followed by placebo to complete the six month time period. | Other: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Between baseline and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | baseline through 7 months | 
| 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. | Between baseline and 12 months | 
| 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. | Between baseline and 24 months | 
| 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) | 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. | Between baseline and 6 months | 
| 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) | 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. | Between baseline and 12 months | 
| 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) | 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. | Between baseline and 24 months | 
| 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) | 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. | Between baseline and 6 months | 
| 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) | 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. | Between baseline and 12 months | 
| 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) | 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. | Between baseline and 24 months | 
| Neurological Impairment at 12 Months of Life Utilizing the Bayley Scales of Infant and Toddler Development (Cognitive Composite Score). | 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. | 12 Months after enrollment | 
| Neurological Impairment at 12 Months of Age Utilizing the Bayley Scales of Infant and Toddler Development (Receptive Communication Scaled Score). | 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. | 12 Months after enrollment | 
| 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. | 12 Months after enrollment | 
| Neurological Impairment at 12 Months of Life Utilizing the Bayley Scales of Infant and Toddler Development (Language Composite Score). | 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. | 12 Months after enrollment | 
| Neurological Impairment at 12 Months of Life Utilizing the Bayley Scales of Infant and Toddler Development (Fine Motor Scaled Score). | 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. | 12 Months after enrollment | 
| Neurological Impairment at 12 Months of Life Utilizing the Bayley Scales of Infant and Toddler Development (Gross Motor Scaled Score). | 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. | 12 Months after enrollment | 
| Neurological Impairment at 12 Months of Life Utilizing the Bayley Scales of Infant and Toddler Development (Motor Composite Score). | 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. | 12 Months after enrollment | 
| Neurological Impairment at 24 Months Utilizing the Bayley Scales of Infant and Toddler Development (Receptive Communication Scaled Score). | 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. | 24 Months after enrollment | 
| Neurological Impairment at 24 Months of Life Utilizing the Bayley Scales of Infant and Toddler Development (Cognitive Composite Score). | 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. | 24 months after enrollment | 
| Neurological Impairment at 24 Months of Life, 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. | 24 Months after enrollment | 
| Neurologic Impairment at 24 Months of Life Utilizing the Bayley Scales of Infant and Toddler Development (Language Composite Score). | 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. | 24 Months after enrollment | 
| Neurological Impairment at 24 Months, Utilizing the Bayley Scales of Infant and Toddler Development (Fine Motor Scaled Score). | 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. | 24 Months after enrollment | 
| Neurological Impairment at 24 Months of Life, Utilizing the Bayley Scales of Infant and Toddler Development (Gross Motor Scaled Score). | 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. | 24 Months after enrollment. | 
| Neurological Impairment at 24 Months of Life, Utilizing the Bayley Scales of Infant and Toddler Development (Motor Composite Score). | 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. | 24 Months after enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cytomegalovirus, congenital, infants