Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants (ValEAR)

Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants: ValEAR Trial

The overall goal of this study is to determine the clinical benefit and safety of antiviral therapy for asymptomatic congenital cytomegalovirus (cCMV) infected hearing-impaired infants. We will conduct a multi-center double-blind randomized placebo-controlled trial to determine whether hearing-impaired infants with asymptomatic cCMV have better hearing and language outcomes if they receive valganciclovir antiviral treatment. We will also determine the safety of antiviral valganciclovir therapy for asymptomatic cCMV-infected hearing impaired infants. This study will be unique in that the cohort enrolled will only include hearing-impaired infants with asymptomatic cCMV.

Primary Objective: To determine if treatment of cCMV-infected hearing impaired infants with isolated hearing loss with the antiviral drug valganciclovir reduces the mean slope of total hearing thresholds over the 20 months after randomization compared to untreated cCMV-infected infants with isolated hearing loss.

Main Secondary Objectives:

1. To determine if valganciclovir treatment improves the following outcomes when compared to the control group:

   1. The slope of best ear hearing thresholds over the 20 months after randomization.
   2. The MacArthur-Bates Communicative Development Inventory (CDI) percentile score for words produced at 20 months of age.
2. To evaluate safety measures based on all grade 3 or greater new adverse events designated by the NIAID Division of AIDS (DAIDS) toxicity tables.

Study Overview

• Status: Terminated
• Conditions: Cmv Congenital; CMV; Congenital Cmv; SNHL; Sensorineural Hearing Loss
• Intervention / Treatment: Drug: Valganciclovir; Drug: Simple Syrup

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital
    • San Diego, California, United States, 92123
      • Rady Children's Hospital - San Diego
    • San Francisco, California, United States, 94158
      • UCSF Benioff Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Lurie Children's Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts Eye and Ear
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Mott Children's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Masonic Children's Hospital
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
    • St Louis, Missouri, United States, 63103
      • Saint Louis Universtiy
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Children's Hospital at Dartmouth-Hitchcock
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico
  • New York
    • Brooklyn, New York, United States, 11203
      • SUNY Downstate Medical Center
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10021
      • Weill Cornell Medicine
    • New York, New York, United States, 11040
      • Cohen Children's Medical Center
    • The Bronx, New York, United States, 10469
      • The Children's Hospital at Montefiore
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Monroe Carell Jr. Children's Hospital at Vanderbilt
  • Texas
    • Dallas, Texas, United States, 75235
      • Ut Southwestern
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Primary Children's Hospital
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Children's Hospital of The King's Daughters
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 1 year (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age greater than or equal to 1 month and less than or equal to 12 months at the time of randomization; 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
• 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; OR
• < 32 weeks gestational age at birth; OR
• Weight at the time of birth < 1800 g.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; Valganciclovir 16 mg/kg PO twice daily (BID) x 6 months	Drug: Valganciclovir; Valganciclovir is supplied as a powder for reconstitution into an oral solution. The reconstituted solution formulation comprises the following excipients: Povidone K30, fumaric acid, sodium benzoate, saccharin sodium, mannitol, flavor, and purified water.; Other Names: Valcyte
Placebo Comparator: Arm B; Flavored Simple Syrup, volume equivalent to active arm dose, PO BID x 6 months	Drug: Simple Syrup; Simple Syrup contains sucrose 85% weight by volume, purified water, and methyl paraben as a preservative along with natural preservatives. It will be flavored to match the flavor of valganciclovir.; Other Names: Sucrose Water

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline Total Ear Hearing Thresholds	Baseline hearing thresholds were summarized descriptively using the average minimum response levels (MRLs) at 2 kHz and 4 kHz for each ear. Lower values indicate better hearing sensitivity.	Baseline assessment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline Best-Ear Hearing Thresholds (2 kHz and 4 kHz)	Baseline best-ear hearing thresholds were summarized descriptively using the average minimum response levels (MRLs) at 2 kHz and 4 kHz. Lower values indicate better hearing sensitivity.	Baseline assessment
MacArthur-Bates Communicative Development Inventories (CDI): Words Produced Percentile Score	The MacArthur-Bates Communicative Development Inventories (CDI) Words Produced subscale is a parent-reported measure of expressive language development. Percentile scores range from 0 to 100, with higher percentile scores indicating better expressive language performance.	20 months of age

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Words Produced Below 10th Percentile	Participants were classified according to whether their MacArthur-Bates Communicative Development Inventories (CDI) Words Produced percentile score was below the 10th percentile. Scores below the 10th percentile indicate increased risk for expressive language delay. The study was terminated early because of slow enrollment; therefore, the prespecified efficacy analyses were not performed, and only descriptive summaries of available data are reported.	14 and 20 months of age assessments
MacArthur-Bates CDI: Words and Sentences Subscale Percentiles	The MacArthur-Bates Communicative Development Inventories (CDI) Words and Sentences subscales assess expressive language development. This outcome summarizes the Complexity, Word Forms, and Mean Length of Utterance percentile scores. Percentile scores range from 0 to 100, with higher scores indicating better expressive language performance.	20 months of age
LittlEARS Auditory Questionnaire Score	The LittlEARS Auditory Questionnaire is a parent-reported measure of auditory development in young children. Raw scores range from 0 to 35, with higher scores indicating better auditory development. Normative values vary by age. Because the study was terminated early by the National Institute on Deafness and Other Communication Disorders (NIDCD) due to slow enrollment, the target sample size was not achieved and the prespecified inferential efficacy analyses were not performed. Only descriptive summaries of available participant data are reported.	Assessments performed at 14 and 20 months of age
Developmental Domain Endpoints	The Ages and Stages Questionnaire, Third Edition (ASQ-3) is a parent-completed developmental screening instrument that evaluates five developmental domains: Communication, Gross Motor, Fine Motor, Problem Solving, and Personal-Social. Each domain is scored separately; higher scores indicate better developmental performance within that domain. Because the study was terminated early by the National Institute on Deafness and Other Communication Disorders (NIDCD) due to slow enrollment, the target sample size was not achieved and the prespecified inferential efficacy analyses were not performed. No ASQ-3 outcome data are reported.	20 months of age
Valganciclovir Pharmacokinetics	Pharmacokinetic (PK) blood samples were collected between Week 2 and Month 6 after randomization to characterize valganciclovir exposure. Because the study was terminated early by the National Institute on Deafness and Other Communication Disorders (NIDCD) due to slow enrollment, the planned PK assays were not completed before study closure. Therefore, no pharmacokinetic results are available for reporting.	From week 2 to month 6 post-randomization
Number of Participants With Viral Resistance Results	Viral resistance testing was planned to evaluate the development of cytomegalovirus (CMV) resistance mutations following valganciclovir treatment. Because the study was terminated early by the National Institute on Deafness and Other Communication Disorders (NIDCD) due to slow enrollment, the planned viral resistance assays were not completed before study closure. Therefore, no viral resistance results are available for reporting.	Month 7 post-randomization
Viral Load	Cytomegalovirus (CMV) viral load testing was planned at baseline, Month 3, and Month 7 after randomization to assess CMV viral burden during and after treatment. Because the study was terminated early by the National Institute on Deafness and Other Communication Disorders (NIDCD) due to slow enrollment, the planned viral load assays were not completed before study closure. Therefore, no viral load results are available for reporting.	Assessed at baseline, Month 3, and Month 7 post-randomization
LittlEARS Auditory Questionnaire Score	The LittlEARS Auditory Questionnaire is a parent-reported measure of auditory development in young children. Raw scores range from 0 to 35, with higher scores indicating better auditory development. Because the study was terminated early by the National Institute on Deafness and Other Communication Disorders (NIDCD) due to slow enrollment, the target sample size was not achieved and the prespecified inferential efficacy analyses were not performed. No analyzable LittlEARS outcome data were available for reporting.	20 months of age (planned assessment)

Collaborators and Investigators

• Sponsor: Albert Park
• Collaborators: Genentech, Inc.; National Institute on Deafness and Other Communication Disorders (NIDCD)
• Investigators: Principal Investigator: Albert Park, MD, University of Utah

Publications and helpful links

General Publications

• Orb QT, Pesch M, Allen CM, Wilkes A, Ahmad I, Alfonso K, Antonio SM, Mithal LB, Brinkmeier JV, Carvalho D, Chan D, Cheng AG, Chi D, Cohen M, Discolo CM, Duran C, Germiller J, Gibson L, Grunstein E, Harrison G, Lee K, Hawley K, Kohlhoff S, Melvin A, MacArthur C, Nassar M, Neff L, Pecha P, Salvatore C, Schoem S, Virgin F, Saunders J, Schleiss M, Smith RJH, Sood S, Park AH. Congenital Cytomegalovirus Testing Outcomes From the ValEAR Trial. Otolaryngol Head Neck Surg. 2024 May;170(5):1430-1441. doi: 10.1002/ohn.670. Epub 2024 Feb 28.

Study record dates

Study Major Dates

• Study Start (Actual): August 31, 2018
• Primary Completion (Actual): August 31, 2022
• Study Completion (Actual): August 31, 2022

Study Registration Dates

• First Submitted: March 13, 2017
• First Submitted That Met QC Criteria: April 4, 2017
• First Posted (Actual): April 11, 2017

Study Record Updates

• Last Update Posted (Actual): August 27, 2026
• Last Update Submitted That Met QC Criteria: August 5, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: valganciclovir
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Infections; Virus Diseases; DNA Virus Infections; Otorhinolaryngologic Diseases; Sensation Disorders; Ear Diseases; Herpesviridae Infections; Hearing Loss; Hearing Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Hearing Loss, Sensorineural; Cytomegalovirus Infections; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Guanine; Hypoxanthines; Purinones; Purines; Ganciclovir; Acyclovir; Valganciclovir
• Other Study ID Numbers: 90760; 1U01DC014706-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No