Prevention of Transplant Atherosclerosis With Everolimus and Anti-cytomegalovirus Therapy

NCT00966836 | Unknown Phase 3

• 1 other identifier: PROTECT 2008-006980-35
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Heart Transplantation; Cardiac Allograft Vasculopathy; Cytomegalovirus Infection

Keywords

Heart Transplantation; Cardiac Allograft Vasculopathy; Cytomegalovirus Infection; Everolimus; Valganciclovir; Mycophenolate

Outcome Measures

Primary Outcomes (1)

• Change in maximal intimal thickness

  one year

Secondary Outcomes (1)

• CMV infection

  one year

Study Arms (4)

Pre-emptive everolimus

EXPERIMENTAL

Drug: Pre-emptive strategy with valganciclovir plus everolimus

Prophylaxis mycophenolate

EXPERIMENTAL

Drug: Prophylaxis with valganciclovir plus mycophenolate

Prophylaxis Everolimus

EXPERIMENTAL

Drug: Prophylaxis with valganciclovir plus everolimus

Pre-emptive mycophenolate

ACTIVE COMPARATOR

Drug: Pre-emptive mycophenolate

Interventions

Pre-emptive strategy with valganciclovir plus everolimus DRUG

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

Pre-emptive everolimus

Prophylaxis with valganciclovir plus mycophenolate DRUG

Patients will receive 3 months of oral valganciclovir with mycophenolate and standard cyclosporine and prednisone for maintenance immunosuppression

Prophylaxis mycophenolate

Prophylaxis with valganciclovir plus everolimus DRUG

Patients will receive valganciclovir for 3 months after transplant. Everolimus plus reduced cyclosporine and prednisone will be used for maintenance immunosuppression

Prophylaxis Everolimus

Pre-emptive mycophenolate DRUG

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

Pre-emptive mycophenolate

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Bologna: lead

Study Sites (1)

Azienda Ospedaliero-Universitaria S Orsola Malpighi

Bologna, Italy

RECRUITING

Related Publications (5)

• 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.

  PMID: 19416774 BACKGROUND

• 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.

  PMID: 17609604 BACKGROUND

• 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.

  PMID: 18091519 BACKGROUND

• Vernooij RW, Michael M, Colombijn JM, Owers DS, Webster AC, Strippoli GF, Hodson EM. Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev. 2025 Jan 14;1(1):CD005133. doi: 10.1002/14651858.CD005133.pub4.

  PMID: 39807668 DERIVED

• Vernooij RW, Michael M, Ladhani M, Webster AC, Strippoli GF, Craig JC, Hodson EM. Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev. 2024 May 3;5(5):CD003774. doi: 10.1002/14651858.CD003774.pub5.

  PMID: 38700045 DERIVED

MeSH Terms

Conditions

Cytomegalovirus Infections

Interventions

Valganciclovir; Everolimus; Mycophenolic Acid

Condition Hierarchy (Ancestors)

Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections

Intervention Hierarchy (Ancestors)

Ganciclovir; Acyclovir; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Sirolimus; Macrolides; Lactones; Organic Chemicals; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids

Central Study Contacts

Luciano Potena, MD PhD

CONTACT

+390516364526; luciano.potena2@unibo.it

Francesco Grigioni, MD PhD

CONTACT

+390516364526; francesco.grigioni@unibo.it

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: August 26, 2009
• First Posted: August 27, 2009
• Study Start: April 1, 2009
• Primary Completion: April 1, 2012
• Last Updated: August 27, 2009

Record last verified: 2009-08

Locations

IT (1)