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

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

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.

Study Overview

• Status: Unknown
• Conditions: Heart Transplantation; Cytomegalovirus Infection; Cardiac Allograft Vasculopathy
• Intervention / Treatment: Drug: Pre-emptive strategy with valganciclovir plus everolimus; Drug: Prophylaxis with valganciclovir plus mycophenolate; Drug: Prophylaxis with valganciclovir plus everolimus; Drug: Pre-emptive mycophenolate

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Luciano Potena, MD PhD; Phone Number: +390516364526; Email: luciano.potena2@unibo.it
• Study Contact Backup: Name: Francesco Grigioni, MD PhD; Phone Number: +390516364526; Email: francesco.grigioni@unibo.it

Study Locations

• Italy
  • Bologna, Italy
    • Recruiting
    • Azienda Ospedaliero-Universitaria S Orsola Malpighi
    • Sub-Investigator: Luciano Potena, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pre-emptive everolimus	Drug: Pre-emptive strategy with valganciclovir plus everolimus; 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
Experimental: Prophylaxis mycophenolate	Drug: Prophylaxis with valganciclovir plus mycophenolate; Patients will receive 3 months of oral valganciclovir with mycophenolate and standard cyclosporine and prednisone for maintenance immunosuppression
Experimental: Prophylaxis Everolimus	Drug: Prophylaxis with valganciclovir plus everolimus; Patients will receive valganciclovir for 3 months after transplant. Everolimus plus reduced cyclosporine and prednisone will be used for maintenance immunosuppression
Active Comparator: Pre-emptive mycophenolate	Drug: Pre-emptive mycophenolate; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in maximal intimal thickness	one year

Secondary Outcome Measures

Outcome Measure	Time Frame
CMV infection	one year

Collaborators and Investigators

• Sponsor: University of Bologna

Publications and helpful links

General Publications

• Potena L, Grigioni F, Magnani G, Lazzarotto T, Musuraca AC, Ortolani P, Coccolo F, Fallani F, Russo A, Branzi A. Prophylaxis versus preemptive anti-cytomegalovirus approach for prevention of allograft vasculopathy in heart transplant recipients. J Heart Lung Transplant. 2009 May;28(5):461-7. doi: 10.1016/j.healun.2009.02.009.
• Potena L, Valantine HA. Cytomegalovirus-associated allograft rejection in heart transplant patients. Curr Opin Infect Dis. 2007 Aug;20(4):425-31. doi: 10.1097/QCO.0b013e328259c33b.
• Hill JA, Hummel M, Starling RC, Kobashigawa JA, Perrone SV, Arizon JM, Simonsen S, Abeywickrama KH, Bara C. A lower incidence of cytomegalovirus infection in de novo heart transplant recipients randomized to everolimus. Transplantation. 2007 Dec 15;84(11):1436-42. doi: 10.1097/01.tp.0000290686.68910.bd.

Study record dates

Study Major Dates

• Study Start: April 1, 2009
• Primary Completion (Anticipated): April 1, 2012

Study Registration Dates

• First Submitted: August 26, 2009
• First Submitted That Met QC Criteria: August 26, 2009
• First Posted (Estimate): August 27, 2009

Study Record Updates

• Last Update Posted (Estimate): August 27, 2009
• Last Update Submitted That Met QC Criteria: August 26, 2009
• Last Verified: August 1, 2009

More Information

Terms related to this study

• Keywords: Heart Transplantation; Everolimus; Cardiac Allograft Vasculopathy; Valganciclovir; Mycophenolate; Cytomegalovirus Infection
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Virus Diseases; Infections; DNA Virus Infections; Herpesviridae Infections; Vascular Diseases; Cytomegalovirus Infections; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Mycophenolic Acid; Everolimus; Valganciclovir
• Other Study ID Numbers: PROTECT 2008-006980-35