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

Condition(s) targeted: Cytomegalovirus Infections

Intervention: Valganciclovir (Drug); Placebo (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Overall contact:
Richard Whitley, Phone: (205) 934-5316

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 94 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.

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 design: Allocation: Randomized, Control: Placebo Control, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Primary outcome: Change in best ear hearing assessments.

Secondary outcome:

Adverse events which lead to permanent discontinuation of valganciclovir therapy or to irreversible outcome of the adverse event.

Neurological impairment utilizing the Bayley Scales of Infant and Toddler Development.

Hearing deterioration over left and right ears.

Change in best ear hearing assessments.

Maximum change in hearing assessments over left and right ears.

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. Post-study surveillance to assess potential incidence of cancer will be conducted for as many subjects as possible. Subjects who can be located will be contacted annually for three years for telephone or clinic questioning about whether subject has been diagnosed with cancer. 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 94 male and female neonates (less than or equal to 30 days) with symptomatic congenital CMV.

Minimum age: N/A. Maximum age: 30 Days. Gender(s): Both.

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

Richard Whitley, Phone: (205) 934-5316

Birmingham Heartlands Hospital, Birmingham B9 5SS, United Kingdom; Not yet recruiting

Bristol Royal Hospital for Children, Bristol BS2 8AE, United Kingdom; Not yet recruiting

Alder Hey Childrens Hospital, Liverpool L12 2AP, United Kingdom; Not yet recruiting

Royal Free And University College Medical School, London NW3 2PF, United Kingdom; Not yet recruiting

St George's Healthcare NHS Trust, London SW17 0QT, United Kingdom; Not yet recruiting

Newcastle General Hospital, Newcastle upon Tyne NE4 6BE, United Kingdom; Not yet recruiting

John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom; Not yet recruiting

University of Alabama at Birmingham, Birmingham, Alabama 35233, United States; Recruiting

University of South Alabama Medical Center, Mobile, Alabama 36604, United States; Recruiting

Arkansas Children's Hospital, Little Rock, Alaska 72202, United States; Recruiting

Los Angeles County USC Medical Center, Los Angeles, California 90033, United States; Recruiting

Children's Hospital of Orange County, Orange, California 92868, United States; Recruiting

Stanford University, Stanford, California 94306, United States; Recruiting

University of California, Los Angeles, Torrance, California 90048, United States; Not yet recruiting

The Children's Hospital - Denver, Colorado, Denver, Colorado 80218, United States; Recruiting

Childrens National Medical Center, Washington, District of Columbia 20010, United States; Recruiting

University of South Florida, Tampa, Florida 33606, United States; Recruiting

Emory University School of Medicine, Atlanta, Georgia 30322, United States; Recruiting

University of Louisville, Louisville, Kentucky 40202, United States; Recruiting

Tulane University, New Orleans, Louisiana 70112, United States; Recruiting

Louisiana State University Health Sciences Center, Shreveport, Louisiana 71103, United States; Recruiting

Johns Hopkins University, Baltimore, Maryland 21287, United States; Recruiting

Children's Hospital Boston, Boston, Massachusetts 02115, United States; Not yet recruiting

University of Minnesota, Minneapolis, Minnesota 55455, United States; Recruiting

University of Mississippi, Jackson, Mississippi 39216-4505, United States; Recruiting

Children's Mercy Hospital, Kansas City, Missouri 64108, United States; Not yet recruiting

Washington University in St. Louis, St. Louis, Missouri 63110, United States; Recruiting

Children's Hospital of Omaha, Omaha, Nebraska 68114, United States; Recruiting

The Children's Hospital at Saint Peter's University Hospital, New Brunswick, New Jersey 08901, United States; Recruiting

Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, United States; Not yet recruiting

Women & Children's Hospital, Buffalo, New York 14222, United States; Not yet recruiting

North Shore-Long Island Jewish Health System, Manhasset, New York 11030, United States; Recruiting

University of Rochester, Rochester, New York 14642, United States; Recruiting

SUNY Upstate Medical University, Syracuse, New York 13210, United States; Not yet recruiting

Carolinas Medical Center, Charlotte, North Carolina 28203, United States; Recruiting

MetroHealth Medical Center, Cleveland, Ohio 44109-1998, United States; Recruiting

The Cleveland Clinic Foundation, Cleveland, Ohio 44195, United States; Recruiting

Columbus Children's Hospital, Columbus, Ohio 43205, United States; Not yet recruiting

Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224, United States; Recruiting

Rhode Island Hospital, Providence, Rhode Island 02903, United States; Recruiting

Medical University of South Carolina, Charleston, South Carolina 29425, United States; Recruiting

Vanderbilt University, Nashville, Tennessee 37232, United States; Recruiting

The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9063, United States; Recruiting

Cook Children's Medical Center, Fort Worth, Texas 76104, United States; Recruiting

University of Utah, Salt Lake City, Utah 84108, United States; Not yet recruiting

Seattle Children's Hospital, Seattle, Washington 98105, United States; Recruiting

Starting date: June 2008
Last updated: September 16, 2010