Prevention of Transplant Atherosclerosis With Everolimus and Anti-cytomegalovirus Therapy (PROTECT)

University of Bologna

Status and phase: Unknown; Phase 3

Conditions: Cardiac Allograft Vasculopathy; Cytomegalovirus Infection; Heart Transplantation

Treatments: Drug: Pre-emptive mycophenolate; Drug: Pre-emptive strategy with valganciclovir plus everolimus; Drug: Prophylaxis with valganciclovir plus mycophenolate; Drug: Prophylaxis with valganciclovir plus everolimus

Study type: Interventional

Funder types: Other

Identifiers

NCT00966836

PROTECT 2008-006980-35

Details and patient eligibility

About

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.

Enrollment: 100 estimated patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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100 participants in 4 patient groups

Pre-emptive everolimus

Experimental group

Treatment:

Drug: Pre-emptive strategy with valganciclovir plus everolimus

Prophylaxis mycophenolate

Experimental group

Treatment:

Drug: Prophylaxis with valganciclovir plus mycophenolate

Prophylaxis Everolimus

Experimental group

Treatment:

Drug: Prophylaxis with valganciclovir plus everolimus

Pre-emptive mycophenolate

Active Comparator group

Treatment:

Drug: Pre-emptive mycophenolate