Clinical trial NCT03107871: Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants
Official title: Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants: ValEAR Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Cmv Congenital
CMV
Congenital Cmv
SNHL
Sensorineural Hearing Loss
Keywords: valganciclovir
Lead sponsor: University of Utah
Sponsor class: OTHER
Collaborators: name: National Institute on Deafness and Other Communication Disorders (NIDCD)
name: Genentech, Inc.
First posted: 2017-04-11
Enrollment: 52
Sex: ALL
Minimum age (years): 1
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Total Ear Hearing Slope
timeFrame: Assessed at baseline, 8, 14 and 20 months post-randomization
Secondary outcomes:
measure: Best Ear Hearing Slope
timeFrame: Assessed at baseline, 8, 14 and 20 months post-randomization
measure: Percentile Score for Words Produced Endpoint
timeFrame: Assessed at 20 months of age
Other outcomes:
measure: Words Produced Below 10th Percentile
timeFrame: 14 and 20 month of age assessments
measure: Additional MacArthur Bates - Words and Sentences Subscale Percentiles
timeFrame: 20 month of age assessment
measure: MacArthur Bates - Words and Gestures Subscale Percentiles
timeFrame: 14 months of age assessment
measure: Developmental Domain Endpoints
timeFrame: 14 and 20 months of age assessments
measure: Valganciclovir Pharmacokinetics
timeFrame: From week 2 to month 6 post-randomization
measure: Viral Resistance
timeFrame: Assessed at month 7 post-randomization
measure: Viral Load
timeFrame: Assessed at baseline month 3, and month 7 post-randomization
measure: LittlEARS
timeFrame: 14 and 20 months of age assessments
Locations:
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital - San Diego
state: California
city: San Francisco
country: United States
facility: UCSF Benioff Children's Hospital
state: California
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Chicago
country: United States
facility: Lurie Children's Hospital
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University School of Medicine
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Boston
country: United States
facility: Massachusetts Eye and Ear
state: Massachusetts
city: Ann Arbor
country: United States
facility: Mott Children's Hospital
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota Masonic Children's Hospital
state: Minnesota
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Saint Louis Universtiy
state: Missouri
city: Lebanon
country: United States
facility: Children's Hospital at Dartmouth-Hitchcock
state: New Hampshire
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Bronx
country: United States
facility: The Children's Hospital at Montefiore
state: New York
city: Brooklyn
country: United States
facility: SUNY Downstate Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Cohen Children's Medical Center
state: New York
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Monroe Carell Jr. Children's Hospital at Vanderbilt
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Norfolk
country: United States
facility: Children's Hospital of The King's Daughters
state: Virginia
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
Study officials:
affiliation: University of Utah
name: Albert Park, MD
role: PRINCIPAL_INVESTIGATOR
References: