Clinical trial NCT00466817: Short-Term vs. Long-Term Valganciclovir Therapy for Symptomatic Congenital CMV Infections
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cytomegalovirus Infection
Keywords: Cytomegalovirus, congenital, infants
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2007-04-27
Enrollment: 109
Sex: ALL
Maximum age (years): 30
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Best Ear Hearing Assessments at 6 Months.
timeFrame: Between baseline and 6 months
Secondary outcomes:
measure: Adverse Events Which Lead to Permanent Discontinuation of Valganciclovir Therapy or Lead to Irreversible Outcome of the Adverse Event.
timeFrame: baseline through 7 months
measure: Change in Best Ear Hearing Assessments at 12 Months.
timeFrame: Between baseline and 12 months
measure: Change in Best Ear Hearing Assessments at 24 Months.
timeFrame: Between baseline and 24 months
measure: 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)
timeFrame: Between baseline and 6 months
measure: 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)
timeFrame: Between baseline and 12 months
measure: 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)
timeFrame: Between baseline and 24 months
measure: 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)
timeFrame: Between baseline and 6 months
measure: 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)
timeFrame: Between baseline and 12 months
measure: 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)
timeFrame: Between baseline and 24 months
measure: Neurological Impairment at 12 Months of Life Utilizing the Bayley Scales of Infant and Toddler Development (Cognitive Composite Score).
timeFrame: 12 Months after enrollment
measure: Neurological Impairment at 12 Months of Age Utilizing the Bayley Scales of Infant and Toddler Development (Receptive Communication Scaled Score).
timeFrame: 12 Months after enrollment
measure: Neurological Impairment at 12 Months of Age Utilizing the Bayley Scales of Infant and Toddler Development (Expressive Communication Scaled Score).
timeFrame: 12 Months after enrollment
measure: Neurological Impairment at 12 Months of Life Utilizing the Bayley Scales of Infant and Toddler Development (Language Composite Score).
timeFrame: 12 Months after enrollment
measure: Neurological Impairment at 12 Months of Life Utilizing the Bayley Scales of Infant and Toddler Development (Fine Motor Scaled Score).
timeFrame: 12 Months after enrollment
measure: Neurological Impairment at 12 Months of Life Utilizing the Bayley Scales of Infant and Toddler Development (Gross Motor Scaled Score).
timeFrame: 12 Months after enrollment
measure: Neurological Impairment at 12 Months of Life Utilizing the Bayley Scales of Infant and Toddler Development (Motor Composite Score).
timeFrame: 12 Months after enrollment
measure: Neurological Impairment at 24 Months Utilizing the Bayley Scales of Infant and Toddler Development (Receptive Communication Scaled Score).
timeFrame: 24 Months after enrollment
measure: Neurological Impairment at 24 Months of Life Utilizing the Bayley Scales of Infant and Toddler Development (Cognitive Composite Score).
timeFrame: 24 months after enrollment
measure: Neurological Impairment at 24 Months of Life, Utilizing the Bayley Scales of Infant and Toddler Development (Expressive Communication Scaled Score).
timeFrame: 24 Months after enrollment
measure: Neurologic Impairment at 24 Months of Life Utilizing the Bayley Scales of Infant and Toddler Development (Language Composite Score).
timeFrame: 24 Months after enrollment
measure: Neurological Impairment at 24 Months, Utilizing the Bayley Scales of Infant and Toddler Development (Fine Motor Scaled Score).
timeFrame: 24 Months after enrollment
measure: Neurological Impairment at 24 Months of Life, Utilizing the Bayley Scales of Infant and Toddler Development (Gross Motor Scaled Score).
timeFrame: 24 Months after enrollment.
measure: Neurological Impairment at 24 Months of Life, Utilizing the Bayley Scales of Infant and Toddler Development (Motor Composite Score).
timeFrame: 24 Months after enrollment
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama - Children's of Alabama - Clinical Virology
state: Alabama
city: Mobile
country: United States
facility: University of South Alabama - Children's Specialty Clinic
state: Alabama
city: Little Rock
country: United States
facility: Arkansas Children's Hospital - Infectious Diseases
state: Arkansas
city: Los Angeles
country: United States
facility: Los Angeles County - University of Southern California - Medical Center - Pediatrics
state: California
city: Los Angeles
country: United States
facility: Plaza Towers Obstetrics and Gynecology
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County - Infectious Diseases
state: California
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado - Infectious Disease
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center - Sheikh Zayed Campus - Infectious Disease
state: District of Columbia
city: Jacksonville
country: United States
facility: University of Florida - College of Medicine - Jacksonville
state: Florida
city: Tampa
country: United States
facility: University of South Florida - Tampa General Hospital - Pediatrics
state: Florida
city: Atlanta
country: United States
facility: Emory Children's Center - Pediatric Infectious Diseases
state: Georgia
city: Louisville
country: United States
facility: University of Louisville School of Medicine - Kosair Childrens Hospital - Infectious Diseases
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University - Tulane Medical Center - Pediatrics
state: Louisiana
city: Shreveport
country: United States
facility: Louisiana State University Health Shreveport - Pediatrics
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins Children's Center - Pediatric Infectious Diseases
state: Maryland
city: Boston
country: United States
facility: Children's Hospital Boston - Infectious Diseases
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota - Pediatric Infectious Disease
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi - Children's Infectious Diseases
state: Mississippi
city: Kansas City
country: United States
facility: Children's Mercy Hospital and Clinics - Infectious Diseases
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine in St. Louis - Center for Clinical Studies
state: Missouri
city: Omaha
country: United States
facility: Creighton University Medical Center - Medicine - Infectious Diseases
state: Nebraska
city: New Brunswick
country: United States
facility: Childrens Hospital at Saint Peters University Hospital - Allergy, Immunology and Infectious Diseases
state: New Jersey
city: New Brunswick
country: United States
facility: Robert Wood Johnson Medical School - Pediatrics
state: New Jersey
city: Buffalo
country: United States
facility: Women & Children's Hospital of Buffalo - Infectious Diseases
state: New York
city: Manhasset
country: United States
facility: Cohen Children's Medical Center - Pediatric Infectious Diseases
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center - Golisano Children's Hospital - Infectious Diseases
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University Hospital - Pediatrics
state: New York
city: Charlotte
country: United States
facility: Carolinas Medical Center - Pediatrics - Infectious Diseases
state: North Carolina
city: Cleveland
country: United States
facility: MetroHealth Medical Center - Pediatric Infectious Disease
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Main Campus - Center for Pediatric Infectious Diseases
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital - Infectious Diseases
state: Ohio
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC - Pediatric Infectious Diseases
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital - Pediatrics
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina - Pediatrics - Infectious Diseases
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University - Pediatric - Infectious Diseases
state: Tennessee
city: Dallas
country: United States
facility: Children's Medical Center Dallas - Neonatal ICU
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center - Pediatrics
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Infectious Disease Services
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah - Pediatric Pharmacology Program
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital - Infectious Diseases
state: Washington
city: Bristol
country: United Kingdom
facility: Bristol Royal Hospital for Children - UBHT Education Centre
state: Bristol, City of
city: London
country: United Kingdom
facility: University College London - Royal Free Campus - Virology
state: London, City of
city: London
country: United Kingdom
facility: Saint George's Hospital - Pediatric Infectious Diseases
state: London, City of
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
state: Oxfordshire
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: Liverpool
country: United Kingdom
facility: Alder Hey Childrens Hospital
city: Newcastle Upon Tyne
country: United Kingdom
facility: Newcastle General Hospital
Study officials:
References:
citation: Kimberlin DW, Jester PM, Sanchez PJ, Ahmed A, Arav-Boger R, Michaels MG, Ashouri N, Englund JA, Estrada B, Jacobs RF, Romero JR, Sood SK, Whitworth MS, Abzug MJ, Caserta MT, Fowler S, Lujan-Zilbermann J, Storch GA, DeBiasi RL, Han JY, Palmer A, Weiner LB, Bocchini JA, Dennehy PH, Finn A, Griffiths PD, Luck S, Gutierrez K, Halasa N, Homans J, Shane AL, Sharland M, Simonsen K, Vanchiere JA, Woods CR, Sabo DL, Aban I, Kuo H, James SH, Prichard MN, Griffin J, Giles D, Acosta EP, Whitley RJ; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl J Med. 2015 Mar 5;372(10):933-43. doi: 10.1056/NEJMoa1404599.