Comparison of Oral Valganciclovir and Placebo for the Prevention of Cytomegalovirus (CMV) After Lung Transplantation

Study Overview
=================
Brief Summary
-----------------
The study evaluated the efficacy and safety of a prolonged, continuous course of Valganciclovir (Valgan) in the prevention of CMV by comparing 3 months of Vaglanciclovir, the standard of care upon initiation of the study, to 12 months of Valganciclovir.

Detailed Description
-----------------
A multi-center two phase, double-blind, placebo controlled, randomized prospective study of 130 lung transplant recipients. Patients will be screened and consented prior to transplant. All consented patients will receive IV ganciclovir within 24 hours of transplant for not more than 14 days. Patients will enroll in Phase I of the study is an open label safety and efficacy analysis of three months of oral valganciclovir in adult transplant recipients who are at risk for CMV. After completion of 3 months of open label therapy, patients that meet the criteria for Phase II of the study will be randomized to 9 months of blinded therapy (Placebo/Valgan). Phase II of the study is designed to assess the efficacy of short course sequential IV ganciclovir followed by oral valganciclovir as compared to the extended period of oral valganciclovir prophylaxis in the prevention of CMV disease in at risk lung transplant recipients

Official Title
-----------------
A Phase III, Randomized, Double-Blind Comparison of Oral Valganciclovir and Placebo for Prevention of CMV After Lung Transplantation

Conditions
-----------------
Cytomegalovirus Infections

Intervention / Treatment
-----------------
* Drug: valganciclovir
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria for Phase I: Adult lung transplant recipients age 18 or older At risk for CMV (donor or recipient serology must be positive for CMV) Adequate hematological and renal function, On intravenous (IV) ganciclovir within 24 hours of surgery Agreement to use effective methods of contraception Negative pregnancy Tolerate oral medications within 2 weeks of transplant Negative baseline CMV PCR Able to understand and sign the informed consent Exclusion Criteria for Phase 1: Repeat transplantation Mechanical ventilation at study entry Oral or intravenous ganciclovir treatment outside the study protocol Invasive fungal infection Participation in another investigational study Acute CMV infection or disease Anti-CMV therapy within 30 days before enrollment Uncontrolled diarrhea or malabsorption Allergic reaction to study drug Required use of prohibited medications Lactating women Pregnancy Renal failure Inclusion Criteria for Phase II: Negative serial post transplant PCRs at day 75 Negative bronchial cultures for CMV Adequate hematological and renal function at day 75 IV ganciclovir for up to 2 weeks post operation and open label up to day 90 Effective contraceptives Negative pregnancy Exclusion Criteria Phase II: Renal failure Serious adverse events (SAE) related to study drug CMV disease (study endpoint) Withdraw consent for Phase II

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Valganciclovir 900 mg QD for 9 months post lung transplant. | Drug: valganciclovir<br>* valgan 900mg QD x 9 months post lung transplant<br>* Other names: valcyte;|
| Placebo Comparator: 2<br>placebo for 9 months post lung transplant | Other: Placebo<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of CMV End Organ Disease | The primary study end point was CMV end-organ disease determined by positive tissue immunostain or characteristic histopathology assessed for within 300 days post randomization. | over the course of 300 days after randomization | 
| Incidence of CMV Syndrome | CMV clinical syndrome, with either positive serum PCR or positive culture for CMV from bronchoalveolar lavage and at least 2 of the following: fever, leukopenia, thrombocytopenia, elevated liver function test results malaise, reduction in pulmonary function (FEV1) greater than 20percent of baseline, or radiographic infiltrate consistent with CMV (all in the absence of other causes) | over the course of 300 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Any CMV Infection | Inclusive of CMV syndrome, disease, or infection not meeting primary end point. | over the course of 300 days post randomization | 
| Biopsy Proven Acute Lung Rejection |  | over the course of 300 days of randomization | 
| Non-CMV Infection | non cmv opportunistic infections | over the course of 300 days after randomization | 
| Severity of Viremia | upon diagnosis of cmv disease, the number of CMV DNA copies/mL as measured by PCR | over the course of 300 days after randomization | 
| Ganciclovir Resistance | UL97 genotyping was done on all positive samples for CMV DNA at 1000 copies/mL, with resistance defined by the presence of 1 or more mutations shown by marker transfer to confer phenotypic ganciclovir resistance | over the course of 300 days post randomization | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Acute rejection, Non-CMV infections, Resistance