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

NCT ID: NCT00466817

Last Updated: 2015-08-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 109 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-06-30
• Study Completion Date: 2013-06-30

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.

Conditions

Cytomegalovirus Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Valganciclovir

Six months of oral Valganciclovir.

Group Type: EXPERIMENTAL

Valganciclovir

Intervention Type: DRUG

Mono-valyl ester pro-drug of ganciclovir, oral solution, provided as a 12 grams of powder containing 5 grams of Valganciclovir free base. The oral solution formulation comprises the following excipients: Providone K30, fumaric acid, sodium benzoate, sodium saccharin, mannitol, flavor, and purified water.

Placebo

Six weeks of oral Valganciclovir followed by placebo to complete the six month time period.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

9 grams of powder which contains no Valganciclovir free base. The oral solution formulation comprises the following excipients: mannitol, lactose anhydrous, fumaric acid, sodium benzoate, saccharin sodium, flavor, and purified water.

Interventions

Placebo

9 grams of powder which contains no Valganciclovir free base. The oral solution formulation comprises the following excipients: mannitol, lactose anhydrous, fumaric acid, sodium benzoate, saccharin sodium, flavor, and purified water.

Intervention Type: OTHER

Valganciclovir

Mono-valyl ester pro-drug of ganciclovir, oral solution, provided as a 12 grams of powder containing 5 grams of Valganciclovir free base. The oral solution formulation comprises the following excipients: Providone K30, fumaric acid, sodium benzoate, sodium saccharin, mannitol, flavor, and purified water.

Intervention Type: DRUG

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

• Maximum Eligible Age: 30 Days
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

University of Alabama - Children's of Alabama - Clinical Virology

Birmingham, Alabama, United States

University of South Alabama - Children's Specialty Clinic

Mobile, Alabama, United States

Arkansas Children's Hospital - Infectious Diseases

Little Rock, Arkansas, United States

Los Angeles County - University of Southern California - Medical Center - Pediatrics

Los Angeles, California, United States

Plaza Towers Obstetrics and Gynecology

Los Angeles, California, United States

Children's Hospital of Orange County - Infectious Diseases

Orange, California, United States

Stanford University School of Medicine

Stanford, California, United States

Children's Hospital Colorado - Infectious Disease

Aurora, Colorado, United States

Children's National Medical Center - Sheikh Zayed Campus - Infectious Disease

Washington D.C., District of Columbia, United States

University of Florida - College of Medicine - Jacksonville

Jacksonville, Florida, United States

University of South Florida - Tampa General Hospital - Pediatrics

Tampa, Florida, United States

Emory Children's Center - Pediatric Infectious Diseases

Atlanta, Georgia, United States

University of Louisville School of Medicine - Kosair Childrens Hospital - Infectious Diseases

Louisville, Kentucky, United States

Tulane University - Tulane Medical Center - Pediatrics

New Orleans, Louisiana, United States

Louisiana State University Health Shreveport - Pediatrics

Shreveport, Louisiana, United States

Johns Hopkins Children's Center - Pediatric Infectious Diseases

Baltimore, Maryland, United States

Children's Hospital Boston - Infectious Diseases

Boston, Massachusetts, United States

University of Minnesota - Pediatric Infectious Disease

Minneapolis, Minnesota, United States

University of Mississippi - Children's Infectious Diseases

Jackson, Mississippi, United States

Children's Mercy Hospital and Clinics - Infectious Diseases

Kansas City, Missouri, United States

Washington University School of Medicine in St. Louis - Center for Clinical Studies

St Louis, Missouri, United States

Creighton University Medical Center - Medicine - Infectious Diseases

Omaha, Nebraska, United States

Childrens Hospital at Saint Peters University Hospital - Allergy, Immunology and Infectious Diseases

New Brunswick, New Jersey, United States

Robert Wood Johnson Medical School - Pediatrics

New Brunswick, New Jersey, United States

Women & Children's Hospital of Buffalo - Infectious Diseases

Buffalo, New York, United States

Cohen Children's Medical Center - Pediatric Infectious Diseases

Manhasset, New York, United States

University of Rochester Medical Center - Golisano Children's Hospital - Infectious Diseases

Rochester, New York, United States

SUNY Upstate Medical University Hospital - Pediatrics

Syracuse, New York, United States

Carolinas Medical Center - Pediatrics - Infectious Diseases

Charlotte, North Carolina, United States

MetroHealth Medical Center - Pediatric Infectious Disease

Cleveland, Ohio, United States

Cleveland Clinic Main Campus - Center for Pediatric Infectious Diseases

Cleveland, Ohio, United States

Nationwide Children's Hospital - Infectious Diseases

Columbus, Ohio, United States

Children's Hospital of Pittsburgh of UPMC - Pediatric Infectious Diseases

Pittsburgh, Pennsylvania, United States

Rhode Island Hospital - Pediatrics

Providence, Rhode Island, United States

Medical University of South Carolina - Pediatrics - Infectious Diseases

Charleston, South Carolina, United States

Vanderbilt University - Pediatric - Infectious Diseases

Nashville, Tennessee, United States

Children's Medical Center Dallas - Neonatal ICU

Dallas, Texas, United States

University of Texas Southwestern Medical Center - Pediatrics

Dallas, Texas, United States

Cook Children's Infectious Disease Services

Fort Worth, Texas, United States

University of Utah - Pediatric Pharmacology Program

Salt Lake City, Utah, United States

Seattle Children's Hospital - Infectious Diseases

Seattle, Washington, United States

Birmingham Heartlands Hospital

Birmingham, Birmingham, United Kingdom

Bristol Royal Hospital for Children - UBHT Education Centre

Bristol, Bristol, City of, United Kingdom

Alder Hey Childrens Hospital

Liverpool, Liverpool, United Kingdom

University College London - Royal Free Campus - Virology

London, London, City of, United Kingdom

Saint George's Hospital - Pediatric Infectious Diseases

London, London, City of, United Kingdom

Newcastle General Hospital

Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom

John Radcliffe Hospital

Oxford, Oxfordshire, United Kingdom

Countries

United States; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 25738669 (View on PubMed)

Other Identifiers

CASG 112

Identifier Type: -

Identifier Source: secondary_id

06-0046

Identifier Type: -

Identifier Source: org_study_id