Valganciclovir in Congenital CMV Infants

Cytomegalovirus Infections Clinical Trial

Official title:

A Phase I/II Pharmacokinetic and Pharmacodynamic Evaluation of Oral Valganciclovir in Neonates With Symptomatic Congenital Cytomegalovirus (CMV) Infection (CASG 109)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00031434
• Other study ID #: 01-595
• Secondary ID: CASG 109
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: March 6, 2002
• Last updated: February 3, 2011
• Start date: July 2002
• Est. completion date: July 2007

Study information

• Verified date: July 2009
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal GovernmentUnited States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate how ganciclovir is metabolized when administered intravenously (by a needle inserted into a vein) following valganciclovir syrup, given by mouth to newborns and young infants with symptoms of congenital (present at birth) cytomegalovirus (CMV) disease. The study also seeks to identify a dose of valganciclovir that provides a comparable blood concentration to ganciclovir present in the blood of newborns with symptomatic congenital CMV disease. All study participants will receive 6 weeks of antiviral therapy (defined as ganciclovir and/or valganciclovir). Infants from 0 to 30 days old will participate in the study for 2 years.

Description:

Recent trials have demonstrated that ganciclovir treatment of neonates with symptomatic congenital cytomegalovirus (CMV) disease involving the central nervous system results in improved hearing function (or maintenance of normal hearing function) and prevents hearing deterioration at 6 months. Furthermore, ganciclovir therapy may prevent hearing deterioration at 1 year. Ganciclovir recipients also have a more rapid resolution of their transaminase elevations and a greater degree of short term growth in weight and head circumference compared with untreated patients. Valganciclovir, the oral product of ganciclovir, has been developed as a syrup formulation and presents the opportunity to treat longer, but pharmacokinetic data are needed in infants first to assure the correct dose is being utilized. This Phase I/II, multi-center, open-label trial will assess the safety/tolerability and pharmacokinetics (ganciclovir concentrations) following administration of oral valganciclovir to neonates with symptomatic congenital CMV disease. A total of 24 patients will be evaluated. All patients entered into this study will receive 6 weeks (42 days) of antiviral therapy (defined as ganciclovir and/or valganciclovir). Two different dose determination strategies will be applied in this protocol. The first is an individual patient approach. The second is a group dose modification strategy. The primary endpoint is pharmacokinetics of ganciclovir following administration of oral valganciclovir syrup. The pharmacokinetics will be assessed by a population approach to PK data analysis. Secondary endpoints are: the pharmacokinetics of valganciclovir following administration of oral valganciclovir; the correlation of ganciclovir plasma concentrations following administration of intravenous ganciclovir and oral valganciclovir syrup with CMV whole blood viral load; lack of vomiting and/or diarrhea associated with the administration of oral valganciclovir syrup; and assessment of toxicity, such as neutropenia, associated with the administration of oral valganciclovir syrup.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: July 2007
• Est. primary completion date: July 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 30 Days

Eligibility

Inclusion Criteria:

• Signed informed consent from parent(s) or legal guardian(s).

• Culture confirmation of cytomegalovirus (CMV) from urine or throat swab specimens.

• Symptomatic congenital CMV disease, as manifest by one or more of the following:

Thrombocytopenia Petechiae Hepatomegaly Splenomegaly Intrauterine growth restriction Hepatitis (elevated transaminases and/or bilirubin) Central nervous system involvement of the CMV disease (such as microcephaly, radiographic abnormalities indicative of CMV CNS disease, abnormal CSF indices for age, chorioretinitis, hearing deficits as detected by brainstem evoked response, 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.

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).

• Creatinine clearance < 10mL/min/1.73 square meters at time of study enrollment.

• Infants known to be born to women who are HIV positive (but HIV testing is not required for study entry).

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cytomegalovirus Infections

Intervention

Drug:
• Valganciclovir
Valganciclovir is a mono-valyl ester pro-drug of ganciclovir, which is rapidly converted to ganciclovir on absorption. Valganciclovir oral syrup formulation for administration will be provided as a 15g powder blend containing 3g valganciclovir base, for constitution in 120 mL amber glass bottles. The beginning oral valganciclovir dose under investigation is 14 mg/kg. The dose of oral valganciclovir syrup will be adjusted for the baby's weight and renal function. Weights upon which dosage will be adjustments will be made will be obtained on study days 1, 7, 14, 21, 28, and 35.
• Ganciclovir
Ganciclovir for intravenous infusion will be provided as sterile, lyophilized powder in sealed vials containing 500 mg ganciclovir for re-constitution. The dose of intravenous ganciclovir is 6 mg/kg. Intravenous ganciclovir will be adjusted for the baby's weight and renal function. Weights upon which dosage adjustments will be made will be obtained on study days 1, 7, 14, 21, 28, and 35. Each dose of intravenous ganciclovir should be given over 1 hour using an intravenous pump.

Locations

Country	Name	City	State
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Stroger Cook Hospital	Chicago	Illinois
United States	MetroHealth Medical Center	Cleveland	Ohio
United States	Ohio State University	Columbus	Ohio
United States	The University of Texas Southwestern Medical Center	Dallas	Texas
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	The University of Texas Medical Branch	Galveston	Texas
United States	University of Florida	Jacksonville	Florida
United States	University of Arkansas	Little Rock	Arkansas
United States	University of Southern California	Los Angeles	California
United States	University of Louisville	Louisville	Kentucky
United States	Schneider Children's Hospital	Manhasset	New York
United States	Tulane University	New Orleans	Louisiana
United States	Creighton University	Omaha	Nebraska
United States	Children's Hospital of Orange County	Orange	California
United States	Washington University in St. Louis	Saint Louis	Missouri
United States	The University of Texas Health Science Center	San Antonio	Texas
United States	Stanford University	Stanford	California
United States	SUNY Upstate Medical University	Syracuse	New York

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pharmacokinetics of ganciclovir following administration of oral valganciclovir syrup. The pharmacokinetics will be assessed by a population approach to PK data analysis.		Day 1: 0.25-0.75, 1-3, 5-7, and 10-12 hours. Day 3: with 2nd dose of IV ganciclovir, before dose, 1 hour, 2-3, 5-7, and 10-12 hours after dose. 1 and 2 weeks post oral valganciclovir: 0.5 after the am dose and 3 hours after the 1st PK.	No
Secondary	Pharmacokinetics of valganciclovir following administration of oral valganciclovir syrup.		Day 1: 0.25-0.75, 1-3, 5-7, and 10-12 hours. 1 and 2 weeks post oral valganciclovir: 0.5 after the am dose and 3 hours after the 1st PK.	No
Secondary	Lack of vomiting and/or diarrhea associated with administration of oral valganciclovir syrup.		Assessed through Day 56.	No
Secondary	Correlation of ganciclovir plasma concentrations following administration of intravenous ganciclovir and oral valganciclovir syrup with CMV whole blood viral load.		Day 1 (prior to dose 1 of valganciclovir), Day 7, Day 14, Day 28, Day 42, Day 56, and 6 months.	No
Secondary	Assessment of toxicity, such as neutropenia, associated with the administration of oral valganciclovir syrup.		Duration of study.	Yes