This is a phase II, open-label trial to evaluate valganciclovir as a treatment to prevent development of sensorineural hearing loss (SNHL) in infants with asymptomatic congenital cytomegalovirus (CMV) infection. The trial will be conducted in two phases - screening of newborns to identify eligible subjects, and treatment of those newborns who have confirmed CMV infection at birth but without outward manifestations of congenital CMV infection. 229 newborns with confirmed CMV infection but without baseline SNHL and who meet all inclusion/exclusion criteria will be enrolled into the treatment phase. Study duration is 5 years. Primary objective of this study is to estimate the proportion of subjects with asymptomatic congenital CMV infection who, following treatment with 4 months of oral valganciclovir, develop SNHL by 6 months of life.
This is a phase II, open-label trial to evaluate valganciclovir as a treatment to prevent development of sensorineural hearing loss (SNHL) in infants with asymptomatic congenital cytomegalovirus (CMV) infection. The trial will be conducted in two phases - screening of newborns to identify eligible subjects, and treatment of those newborns who have confirmed CMV infection at birth but without outward manifestations of congenital CMV infection. Approximately 48,250 newborn infants with no outward manifestations of congenital CMV infection will be screened to detect approximately 241 neonates with asymptomatic congenital CMV infection; these 241 newborns then will have audiology examinations to determine baseline hearing, with approximately 229 having normal hearing in both ears. Those 229 newborns with confirmed CMV infection but without baseline SNHL and who meet all inclusion/exclusion criteria will be enrolled into the treatment phase. Enrolled subjects will be treated for four months with oral valganciclovir (16 mg/kg/dose, administered two times per day). Audiologic assessments will be made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. Treated infants will be followed for safety throughout the first 6 months of the study (including for 2 months post-treatment). Study duration is 5 years. Primary objective of this study is to estimate the proportion of subjects with asymptomatic congenital CMV infection who, following treatment with 4 months of oral valganciclovir, develop sensorineural hearing loss (SNHL) by 6 months of life. Secondary objectives are to: 1) define the safety and tolerability of valganciclovir in enrolled subjects, 2) estimate the proportion of subjects with asymptomatic congenital CMV infection who, following treatment with 4 months of oral valganciclovir, develop SNHL over the first 18 months of life.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
7
Valganciclovir, 16 mg/kg/dose given orally twice daily for four months
University of Alabama - Children's of Alabama - Clinical Virology
Birmingham, Alabama, United States
Arkansas Children's Hospital - Infectious Diseases
Little Rock, Arkansas, United States
University of Louisville School of Medicine - Norton Children's Hospital - Infectious Diseases
Louisville, Kentucky, United States
University of Mississippi - Children's Infectious Diseases
Jackson, Mississippi, United States
Washington University School of Medicine in St. Louis - Center for Clinical Studies
St Louis, Missouri, United States
Carolinas Medical Center - Pediatrics - Infectious Diseases
Charlotte, North Carolina, United States
Nationwide Children's Hospital - Neonatology - Center for Perinatal Research
Columbus, Ohio, United States
Children's Hospital of Pittsburgh of UPMC - Pediatric Infectious Diseases
Pittsburgh, Pennsylvania, United States
Texas Medical Center - Texas Children's Hospital
Houston, Texas, United States
The Number of Participants Developing Sensorineural Hearing Loss (SNHL) in at Least One Ear Between Baseline and Study Month 6
Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each subject and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels). SNHL between baseline and Study Month 6 is defined as both ears with normal hearing at baseline, then at least one ear with sensorineural hearing loss (SNHL) at the 6 month follow-up.
Time frame: Between baseline and study month 6
Number of Participants With Absolute Neutrophil Counts Below 500/mm^3
Blood was collected for assessments of hematology and absolute neutrophil count was assessed at each study visit through Month 5
Time frame: Day 1 through Study month 5
Number of Participants With Adverse Events Leading to Permanent Discontinuation of Valganciclovir Therapy, or Any Adverse Event That is Not Recovered / Not Resolved
A count of participants discontinued from valganciclovir therapy due to adverse events were reported during the therapy period, and the count of participants with adverse events not recovered/not resolved were reported throughout the adverse event period.
Time frame: Day 1 through Study month 6
Number of Participants With Grade 3 or Higher Safety Laboratory Adverse Events
At each study visit from the receipt of first dose of study drug and continuing through four weeks following the final dose of study drug, the participants were assessed for any adverse events. Lab parameters included ALT, creatinine, direct bilirubin, white blood cell count with differential, hemoglobin, platelets count. Abnormal laboratory values were reported as an AE if they worsened in severity from baseline, per the grading definitions provided in the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events.
Time frame: From day 1 through study month 6
Number of Participants With Serious Adverse Events
Serious adverse events were those defined as: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect, or were important medical events that may not result in death, be life-threatening, or require hospitalizations may be considered serious when, based upon appropriate medical judgment they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
Time frame: From day 1 through study month 6
Number of Participants With Grade 3 or Higher Unsolicited Adverse Events Assessed by Adapted From DAIDS Toxicity Tables
At each study visit from the receipt of first dose of study drug and continuing through four weeks following the final dose of study drug, the participants were assessed for any adverse events. Lab parameters included ALT, creatinine, direct bilirubin, white blood cell count with differential, hemoglobin, platelets count. Abnormal laboratory values were reported as an AE if they worsened in severity from baseline, per the grading definitions provided in the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events.
Time frame: From day 1 through study month 6
Number of Participants With Mild Worsened Hearing, Represented by the Ear That Has the Larger Degree of Worsening
Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each participant and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels). SNHL between baseline and Study Month 18 is defined as both ears with normal hearing at baseline, then at least one ear with sensorineural hearing loss (SNHL) at the 18 month follow-up.
Time frame: Screening and Study Months 4, 6, 8 and 12
Number of Participants With Moderate Worsened Hearing, Represented by the Ear That Has the Larger Degree of Worsening
Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each subject and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels). SNHL between baseline and Study Month 18 is defined as both ears with normal hearing at baseline, then at least one ear with sensorineural hearing loss (SNHL) at the 18 month follow-up.
Time frame: Screening and Study Months 4, 6, 8 and 12
Number of Participants With Profound Worsened Hearing, Represented by the Ear That Has the Larger Degree of Worsening
Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each participant and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels). SNHL between baseline and Study Month 18 is defined as both ears with normal hearing at baseline, then at least one ear with sensorineural hearing loss (SNHL) at the 18 month follow-up.
Time frame: Study Months 4, 6, 8 and 12
Number of Participants With Severe Worsened Hearing, Represented by the Ear That Has the Larger Degree of Worsening
Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each participant and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels). SNHL between baseline and Study Month 18 is defined as both ears with normal hearing at baseline, then at least one ear with sensorineural hearing loss (SNHL) at the 18 month follow-up.
Time frame: Study Months 4, 6, 8 and 12
Number of Participants With Sensorineural Hearing Loss in at Least One Ear Through Study Month 4
Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each participant and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels). SNHL between baseline and Study Month 4 is defined as both ears with normal hearing at baseline, then at least one ear with sensorineural hearing loss (SNHL) at the 4 month follow-up.
Time frame: Between screening and study month 4
Number of Participants With Sensorineural Hearing Loss in at Least One Ear Through Study Month 12
Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each participant and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels). SNHL between baseline and Study Month 12 is defined as both ears with normal hearing at baseline, then at least one ear with sensorineural hearing loss (SNHL) at the 12 month follow-up.
Time frame: Between screening and study month 12
Number of Participants With Sensorineural Hearing Loss in at Least One Ear Through Study Month 18
Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each participant and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels). SNHL between baseline and Study Month 18 is defined as both ears with normal hearing at baseline, then at least one ear with sensorineural hearing loss (SNHL) at the 18 month follow-up.
Time frame: Between screening and study month 18
Number of Participants With Transaminase Elevation During Treatment > / = 2 Times the Baseline Value
Blood was collected for assessments of clinical chemistry and alanine aminotransferase (ALT) was assessed at screening, week 2, Week 4, Week 6, Week 8, Week 10, Week 12, Month 4, Month 5, and Month 6
Time frame: Baseline, weeks 2, 4, 6, 8, 10, 12, months 4, 5 and 6.
Number of Ears of Mild Worsened Hearing
Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each participant and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels).
Time frame: Screening and Study Months 4, 6, 12, and 18
Number of Ears of Moderate Worsened Hearing
Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each participant and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels).
Time frame: Screening and Study Months 4, 6, 12, and 18
Number of Ears of Profound Worsened Hearing
Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each participant and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels).
Time frame: Screening and Study Months 4, 6, 12, and 18
Number of Ears of Severe Worsened Hearing
Audiologic assessments were made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. A single, independent study audiologist assessed the audiology test battery for each participant and assigned each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels).
Time frame: Screening and Study Months 4, 6, 12, and 18
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