Prevention of Transplant Atherosclerosis With Everolimus and Anti-cytomegalovirus Therapy

Study Overview
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Brief Summary
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Cardiac allograft vasculopathy (CAV) is the major cause of long-term graft failure in heart transplant recipients. Although several immune-mediated and metabolic risk factors have been implicated in the pathogenesis of CAV, no effective therapy is currently available to treat established CAV and prevent its adverse outcomes. Therefore, the main clinical strategy is based on prevention and treatment of factors known to trigger its development. Although the mechanism is vague, cytomegalovirus (CMV) infection is believed to play a key role in CAV progression. Two strategies involving administration of specific anti-CMV agents are recommended for prevention of CMV infection/disease: universal prophylaxis and preemptive therapy. The pros and cons of the two strategies are still debated, in the absence of randomized studies addressing graft-related outcomes and viral mechanisms of graft damage, and without any clear evidence of superiority of either approach. The investigators conceived this randomized prospective project to compare the effect of preemptive anti-CMV strategy with universal anti-CMV prophylaxis on CMV infection and on one-year increase in coronary intimal thickening. Patients will be additionally randomized to receive either mycophenolate mofetil or everolimus, in light of the possible anti-CMV properties of everolimus.

Official Title
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Efficacy and Safety of Anti-cytomegalovirus Prophylaxis Versus Pre-emptive Approaches With Valganciclovir in Heart Transplant Recipients Treated With Everolimus or Mycophenolate. A Randomized Open-label Study for Prevention of Cardiaca Allograft Vasculopathy

Conditions
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Heart Transplantation, Cardiac Allograft Vasculopathy, Cytomegalovirus Infection

Intervention / Treatment
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* Drug: Pre-emptive strategy with valganciclovir plus everolimus
* Drug: Prophylaxis with valganciclovir plus mycophenolate
* Drug: Prophylaxis with valganciclovir plus everolimus
* Drug: Pre-emptive mycophenolate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18y Heart or heart-kidney combined transplant Positive CMV serology at the time of transplant Glomerular filtration rate ≥ 20 ml/min/1.73m2 with MDRD at randomization. Written informed consent Exclusion Criteria: Panel Reactive Antibody ≥50% Less than 1000/mmc neutrophils at the time of randomization Less than 30,000/mmc platelets at the time of randomization Clinical significant infection in the 2 weeks prior to transplant Glomerular filtration rate < 20 ml/min/1.73m2 estimated with MDRD formula at the time of randomization or hemodialysis treatment Intolerance towards valganciclovir, everolimus, mycophenolate or cyc-losporine Known contraindication to statin use Negative CMV serology at the time of transplant HIV positive testing Severe comorbidities that, based on investigator's judgment, contraindicate study drugs or procedures Potentially childbearing women who refuse to use contraceptives Participation to an interventional study in the 2 preceding weeks Unwillingness or inability to follow study procedure and to sign written in-formed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pre-emptive everolimus<br> | Drug: Pre-emptive strategy with valganciclovir plus everolimus<br>* Patients will be monitored for CMV infection and receive valganciclovir only for positive PCR or antigenemia. Everolimus plus cyclosporine and prednisone will be used for maintenance immunosuppression<br>|
| Experimental: Prophylaxis mycophenolate<br> | Drug: Prophylaxis with valganciclovir plus mycophenolate<br>* Patients will receive 3 months of oral valganciclovir with mycophenolate and standard cyclosporine and prednisone for maintenance immunosuppression<br>|
| Experimental: Prophylaxis Everolimus<br> | Drug: Prophylaxis with valganciclovir plus everolimus<br>* Patients will receive valganciclovir for 3 months after transplant. Everolimus plus reduced cyclosporine and prednisone will be used for maintenance immunosuppression<br>|
| Active Comparator: Pre-emptive mycophenolate<br> | Drug: Pre-emptive mycophenolate<br>* Patients will be monitored for CMV infection and receive valganciclovir only for positive PCR or antigenemia. Mycophenolate plus standard cyclosporine and prednisone will be used for maintenance immunosuppression<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in maximal intimal thickness |  | one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CMV infection |  | one year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Transplantation, Cardiac Allograft Vasculopathy, Cytomegalovirus Infection, Everolimus, Valganciclovir, Mycophenolate