Prevention of Transplant Atherosclerosis With Everolimus and Anti-cytomegalovirus Therapy

Heart Transplantation Clinical Trial

— PROTECT  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00966836
• Other study ID #: PROTECT 2008-006980-35
• Status: Recruiting
• Phase: Phase 3
• First received: August 26, 2009
• Last updated: August 26, 2009
• Start date: April 2009

Study information

• Verified date: August 2009
• Source: University of Bologna
• Contact: Luciano Potena, MD PhD
• Phone: +390516364526
• Email: luciano.potena2[@]unibo.it
• Is FDA regulated: No
• Health authority: Italy: Agenzia Italiana del Farmaco (AIFA)
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. primary completion date: April 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Cardiac Allograft Vasculopathy
• Cytomegalovirus Infection
• Cytomegalovirus Infections
• Heart Transplantation
• Vascular Diseases

Intervention

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

Locations

Country	Name	City	State
Italy	Azienda Ospedaliero-Universitaria S Orsola Malpighi	Bologna

Sponsors (1)

Lead Sponsor	Collaborator
University of Bologna

Country where clinical trial is conducted

Italy, 

References & Publications (3)

Hill JA, Hummel M, Starling RC, Kobashigawa JA, Perrone SV, Arizón 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. — View Citation

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. — View Citation

Potena L, Valantine HA. Cytomegalovirus-associated allograft rejection in heart transplant patients. Curr Opin Infect Dis. 2007 Aug;20(4):425-31. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in maximal intimal thickness		one year	No
Secondary	CMV infection		one year	No