Viewing Study NCT00225394



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Last Modification Date: 2024-10-26 @ 9:19 AM
Study NCT ID: NCT00225394
Status: COMPLETED
Last Update Posted: 2005-09-23
First Post: 2005-09-21

Brief Title: Long Term Use of Valganciclovir for Prophylaxis of CMV Disease in Kidney and Pancreas Transplant Patients
Sponsor: University of Massachusetts Worcester
Organization: University of Massachusetts Worcester

Study Overview

Official Title: Long-Term Valcyte Therapy in Transplant Patients and the Development of Ganciclovir Resistant CMV
Status: COMPLETED
Status Verified Date: 2005-08
Last Known Status: None
Delayed Posting: No
If Stopped, Why?: Not Stopped
Has Expanded Access: No
If Expanded Access, NCT#: N/A
Has Expanded Access, NCT# Status: N/A
Acronym: None
Brief Summary: CMV viral disease negatively affects transplant patients CMV is the most prevalent infection in transplant patients and 3 month drug regimens to prevent the virus have been mostly unsuccessful usually after the drug has been stopped the patient develops the viral disease Extended use of anti-viral drugs may in fact may lead to the development of resistant virus We hypothesize that extended use 12 months of valganciclovir Valcytewill not only be efficacious but will not be associated with the development of resistant CMV

Sample Size 100 patients at 3 sites have been enrolled

Patient Selection Adult 18 years recipients of cadaveric or living donor kidneys pancreas or combine kidney-pancreas transplants

Immunosuppression To be determined according to each centers standard protocol s

Study Drug Valcyte Days 0 - 90 All Patients 900 mg QD

Days 91 - 365

Group 1 900 mg QD Group 2 450 mg QD

Assessment of Valgancicovir ValcyteResistant CMV Serial serum samples at transplant 6 weeks and 3 6 9 and 12 months post-transplant for PCR amplification and DNA sequence analysis from detectable CMV to identify the presence of mutations within the UL97 and UL54 genes

Other Analyses

Additional information will be evaluated relating to the development of CMV disease development of ganciclovir toxicity graft rejection or graft loss and patient death Preliminary information regarding the predictive value of DNA assays for the development of CMV disease will be evaluated
Detailed Description: CMV infection occurs most frequently in the first three months following transplantation and following treatment for acute rejection both instances can be related to relatively high levels of immunosuppression relative to stable long-term allograft recipients Disease then can occur and is manifest as fever low white blood cell count pneumonitis gastroenteritis hepatitis retinitis and a multitude of other symptoms

Ganciclovir a potent inhibitor of the herpesviridae DNA polymerase encoded for on the unique long UL54 region of the CMV genome has had a significant impact on both the prophylaxis and treatment of CMV infection in transplant patients CMV-infected cells produce a phosphotransferase or kinase UL97 region that phosphorylates ganciclovir to ganciclovir-triphosphate The triphosphate product inhibits CMV replication by competitively inhibiting the incorporation of deoxyguanine triphosphate dGTP into the DNA region encoding the polymerase UL54 region thus resulting in the premature termination of viral DNA synthesis Resistance to ganciclovir is conferred when mutations occur on the UL97 region of the CMV genome

Ganciclovir is available in either an oral or an intravenous formulation The obvious advantages of the oral formulation are somewhat offset by the fact that its bioavailability is only 8 to 10 The product has been reformulated with the addition of an L-valyl ester the resulting compound valganciclovir Valcyte is metabolized to ganciclovir and has a 3 to 7 fold increase in bioavailability and is able to maintain serum concentrations equivalent to the intravenous formulation This provides a convenient method for obtaining therapeutic concentrations of ganciclovir for extended periods of time without the need for in-dwelling intravenous lines

The optimal length of treatment has not been established and relapse rates as high as 25 are common upon cessation of the antiviral agent6 Patients with CMV disease are initially treated with intravenous ganciclovir for two or more weeks and then with an oral agent for many weeks thereafter Current laboratory technology allows detection of active viral replication either through the detection of the pp65 antigen on the surface of infected leukocytes or through the use PCR amplification for the detection of viral DNA It is however still unclear whether the best therapeutic option is to treat until symptoms disappear or to treat until evidence of active viral replication ceases

The question of whether or not prolonged exposure to ganciclovir will result in an increase in the incidence of resistant CMV strains has not been answered There is also a theoretical increase in the risk of selection pressure for resistant CMV when the lower dose of valganciclovir 450 mg is used This proposal will document the emergence of ganciclovir-resistant strains of CMV in high-risk kidney pancreas or combined kidneypancreas transplant patients receiving long-term suppressive therapy with Valcyte and will also address the issue of selection pressure by randomizing for low and high dose valganciclovir prophylaxis Emergence of resistance will be defined as detection of a resistance-conferring mutation in the UL97 phosphotransferase or UL54 DNA polymerase open reading frame of detectable CMV

Objectives

Primary

To document

1 The emergence of ganciclovir-resistant CMV by PCR amplification and DNA sequence analysis for detecting resistance-conferring mutations of UL97 andor UL54 open reading frames
2 The development and time-to-onset of CMV disease

Secondary

To document

1 The development of ganciclovir toxicity
2 Loss of kidney andor pancreas graft function
3 Patient death

Tertiary

To attempt to determine the predictive value of DNA assays for the development of CMV disease

Study Design

This will be a phase 4 4 center and randomized pilot study Kidney pancreas or combined kidneypancreas transplant patients that receive induction anti-thymocyte globulin or OKT3 andor are either seropositive for CMV or receive a graft from a CMV seropositive donor will receive Valcyte 900 mg daily for 90 days Patients will then be randomized to either 450 mg or 900 mg Valcyte each day for days 91 to 365 Patients will be serially monitored for the development of ganciclovir-resistant CMV Patients will receive standard immunosuppression antibacterial and antifungal prophylaxis and other necessary medications as determined by their physicians

Statistical Analysis

Primary Endpoints Time to development of any CMV disease or emergence of ganciclovir-resistant CMV

Methods Kaplan-Meier product limit estimates for median time to CMV disease for both treatment groups will be used and a Kaplan-Meier survival curve will be plotted to compare treatment difference Kaplan-Meier product limit estimates for median time to CMV resistance for both treatment groups will be used and a Kaplan-Meier survival curve will be plotted to compare treatment difference In addition the Cox regression will be performed to compare treatment groups using treatment as a covariate in the model

Secondary Endpoints Incidence of ganciclovir toxicity loss of kidney andor pancreas and patient death

Methods Cox regression will be performed to compare treatment groups using treatment and incidence of resistance as covariates in the model Fishers exact test will be used to analyze the loss of kidney andor pancreas allograft function and patient mortality Toxicity within the two prophylaxis cohorts will be compared using Fishers exact test also

Tertiary Endpoint Efficacy of DNA assay to predict CMV disease Method A two-tailed t test comparison will be used to test the hypothesis that high copy numbers of CMV DNA correlate with the development of CMV disease Additionally a test based on a Cox proportional hazard model will be used to assess other variables and their impact on the development of CMV resistance and their relationship to copy numbers of DNA

The above parameters will be assessed at three time points6 months from the initiation of the trial at 12 months post enrollment for each patient and again at 24 months post-enrollment

Materials and Methods

Definitions of CMV CMV Infection

CMV infection is defined as the isolation or identification of CMV from any site blood urine sputum stool positive seroconversion presence of positive CMV IgM or a four-fold increase in the titer of CMV IgG or evidence of CMV viral replication pp65 antigenemia or positive CMV by PCR amplification techniques in the absence of clinical symptoms

CMV Syndrome

CMV syndrome is defined as a virologically confirmed illness with any of the following fever pneumonia leukopenia lymphocytosis thrombocytopenia serum alanine aminotranferase levels 25 x normal with or without flu-like manifestations of viral immunity malaise myalgias arthralgias anorexia nausea vomiting Any patient presenting with any of these signs or symptoms at any time during this study will have blood body fluid andor biopsy specimen sent for viral confirmation which may include any of the following studies histology for the presence of inclusion bodies immunofluorescence of antibody to pp65 antigen or qualitative presence of CMV genome by PCR amplification

CMV Disease

CMV disease will be defined as CMV infection and syndrome with any of the following evidence of host cellular viral inclusions on biopsy or body fluid for cytology a positive conventional viral culture for CMV a positive rapid antigen test for the presence of pp65 antigen on the cell surface of buffy coat leukocytes or the qualitative presence of CMV DNA as analyzed by PCR amplified virus Specimens used for the above diagnostic procedures may include blood liver or lung biopsy endoscopic mucosal biopsy or brushing bronchoalveolar lavage or cerebrospinal fluid

Severe CMV Disease

Severe CMV disease is defined as CMV disease in two or more organs or one or more of the following CMV pneumonia CMV retinitis CMV CNS involvement and invasive fungal or parasitic disease in association with CMV infection of any sort

CMV Mortality

CMV mortality is defined as any death due to symptomatic CMV disease or death from any opportunistic infection while there is evidence of CMV disease or ongoing CMV viral replication

Ganciclovir Resistant CMV

Ganciclovir resistant CMV is defined as the detection of a resistance-conferring mutation of the UL97 andor the UL54 open reading frame by DNA sequence analysis of PCR amplified CMV genome

Valganciclovir Valcyte

Valcyte is a product of Roche Laboratories Nutley New Jersey Patients will receive 450 or 900 mg per day depending on the stage of the study and the individuals randomization Dosage will be adjusted for renal insufficiency as per package insert If creatinine clearance crcl is 60 mlmin no adjustment is needed If crcl is 40-59 patients can only receive up to 450 mg once daily Therefore those randomized to the 900mgday cohort will receive 450 mg and those randomized to receive 450 mgday will receive 450 mg every other day QOD If creatinine clearance is less than 40 and will never improve patients will be excluded or terminated from the study

Immunosuppression

Immunosuppressive medications will be administered according to the protocols in place at each participating center The choice of maintenance immunosuppression and treatment for rejection will be at the discretion of the centers principal investigator

Concomitant Anti-infectives

Patients enrolled in the study will receive anti-bacterial and anti-fungal prophylaxis as determined by the protocol in place for their transplanted organ at their transplant center The use of antibiotics and anti-fungals for the treatment of disease will be at the discretion of the individual patients physician

Hematopoietic Growth Factors

Regrastim GM-CSF Prokine Hoechst-Roussel and Leukine Immunex and filgrastim G-CSF Neupogen Amgen may be used at the discretion of the physician for the treatment of leukopenia including ganciclovir-related leukopenia

Study Oversight

Has Oversight DMC: None
Is a FDA Regulated Drug?: None
Is a FDA Regulated Device?: None
Is an Unapproved Device?: None
Is a PPSD?: None
Is a US Export?: None
Is an FDA AA801 Violation?: None